CN103113463B - 核重新编程因子 - Google Patents
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Abstract
作为用于不利用胚和ES细胞而诱导分化细胞的重新编程,简便且再现性强地建立具有与ES细胞同样的多能性和增殖能力的诱导式多能性干细胞的方法,本发明提供了含有下述3种基因:Oct家族基因、Klf家族基因和Myc家族基因的各基因的产物的体细胞的核重新编程因子。
Description
本申请是申请号200680048227.7、申请日为2006年12月6日的同名申请的分案申请。
技术领域
本发明涉及具有使分化的体细胞重新编程来诱导诱导式多能性干细胞的作用的核重新编程因子(nuclear reprogramming factor)。
背景技术
胚胎干细胞(ES细胞)是由人和小鼠的初期胚建立的干细胞,具有能长期进行培养并维持可以分化成存在于生物体中的所有类型细胞的多能性的特征。人们期待利用该性质将人ES细胞作为针对帕金森病、青少年糖尿病、白血病等多种疾病的细胞移植疗法的来源。但是,存在着ES细胞的移植与脏器移植同样会引起排斥反应这样的问题。而且,对于通过破坏人胚胎建立的ES细胞的利用,出于伦理的观点的反对意见也很多。如果能够诱导患者自身的分化体细胞脱分化,建立具有接近于ES细胞的多能性和增殖能力的细胞(该细胞在本说明书中被称为“诱导式多能性干细胞”(iPS细胞),但也存在被称为“胚胎干细胞样细胞”或“ES样细胞”的情况)的话,则预期能够利用它们作为没有排斥反应和伦理性问题的理想的多能性细胞。
作为使体细胞核重新编程的方法,已报道了,例如,从将体细胞的核移植到***中制备的克隆胚中建立ES细胞的技术(W.S.Hwang等,Science,303,pp.1669-74,2004;W.S.Hwang等,Science,308,pp.1777-83,2005:但是,现已清楚了这些论文都是捏造的,而且已于日后撤下这些论文)。然而,这些技术只是为了建立ES细胞的目的而制备克隆胚,因此与使用***治疗中产生的剩余胚的常规ES细胞相比,伦理的问题反而大。而且,现已报道了通过使体细胞与ES细胞相融合使体细胞核重新编程的技术(M.Tada等,Curr.Biol.,11,pp.1553-1558,2001;C.A.Cowan等,Science,309,pp.1369-73,2005)。但是,即使在该方法中也存在以下问题:无法解决由于导致最终使用人ES细胞而产生的伦理性问题。而且,现已报道了使生长于人中的生殖细胞肿瘤来源的细胞株的提取物和分化细胞反应而使细胞核重新编程的技术(C.K.Taranger等,Mol.Biol.Cell,16,pp.5719-35,2005)。该方法,提取物中何种成分诱导重新编程完全不清楚,因此在技术的可靠性和安全性上存在问题。
另一方面,提出了筛选具有使分化的体细胞重新编程来诱导诱导式多能性干细胞的作用的核重新编程因子的方法(国际公开WO2005/80598)。该方法包括以下步骤:使含有在受ECAT(ES cellassociated transcript)基因(ES细胞中特异性表达的基因群:ES细胞相关转录物)的表达调节区域的表达调节位置上存在标记基因的基因的体细胞与被检物质相接触、研究标记基因表达细胞的出现的有无,选择使该细胞出现的被检物质作为体细胞的核重新编程因子的候选物。而且,该出版物的实施例6等中公开了使体细胞重新编程的方法。但是,上述出版物中没有公开实际上鉴定核重新编程因子的报告。
专利文献1国际公开WO2005/80598
发明内容
本发明的课题在于提供核重新编程因子。更具体的是,本发明的课题在于提供用于不利用***、胚和ES细胞而诱导分化细胞的重新编程,简便且再现性强地建立具有与ES细胞同样的多能性和增殖能力的诱导式多能性干细胞的方法。
本发明者为了解决上述的课题进行了积极的研究,使用国际公开WO2005/80598中记载的核重新编程因子的筛选方法尝试鉴定核重新编程因子。其结果是,发现了24种候选作为与核重新编程相关的基因,确认了它们中的3种基因是核重新编程所必需的基因。本发明是基于上述发现而完成的。
也就是,根据本发明,提供了一种体细胞的核重新编程因子,其含有下述3种基因:Oct家族基因、Klf家族基因和Myc家族基因的各基因的产物。根据本发明的优选方式,提供了含有下述3种基因:Oct3/4、Klf4和c-Myc的各基因的产物的上述因子。
而且,根据其它的优选方式还提供了还含有下述基因:Sox家族基因的基因产物的上述因子,作为更优选的方式,提供了含有Sox2的基因产物的上述因子。
而且,如果根据其它的优选方式,提供了含有细胞因子,该细胞因子和Myc家族基因的基因产物共同存在、或代替Myc家族基因的基因产物。作为更优选方式,提供了细胞因子为碱性成纤维细胞生长因子(bFGF)和/或干细胞因子(SCF)的上述因子。
如果根据特别优选的方式,提供了除Oct家族基因、Klf家族基因、Myc家族基因、和Sox家族基因的各基因的产物之外,还含有TERT基因的基因产物的体细胞的核重新编程因子;以及除了Oct家族基因、Klf家族基因、Myc家族基因、Sox家族基因,和TERT基因的各基因的产物之外,还含有从由下述的基因:SV40大T抗原、HPV16E6、HPV16E7和Bmil构成的组中选出的一种以上的基因产物的因子。
除了这些因子,还提供了进一步含有选自于下组中的1种以上的基因的基因产物的上述的因子:Fbx15、Nanog、ERas、ECAT15-2、Tcl1和β-连环素(catenin)。
而且,如果根据上述发明的其它优选方式,还提供了进一步含有选自于下组中的1种以上的基因的基因产物的上述的因子,所述组为:ECAT1、Esg1、Dnmt3L、ECAT8、Gdf3、Sox15、ECAT15-1、Fthl17、Sall4、Rex1、UTF1、Stella、Stat3和Grb2。
从其它的观点出发,本发明提供了通过体细胞的核重新编程制备诱导式多能性干细胞的方法,该方法包括使上述的核重新编程因子与体细胞接触的步骤。
如果根据本发明的优选方式,提供了包括在体细胞的培养物中添加上述的核重新编程因子的步骤的上述方法;包括在体细胞中导入编码上述的核重新编程因子的基因的步骤的上述方法;包括使用含有至少1种以上的编码上述核重新编程因子的基因的重组载体将该基因导入体细胞中的步骤的上述方法;和使用从患者中采集的体细胞作为体细胞的上述方法。
再从其它的观点出发,本发明提供了由上述方法获得的诱导式多能性干细胞。而且,本发明还提供了诱导上述的诱导式多能性干细胞分化而得到的体细胞。
而且,根据本发明,还提供了一种干细胞疗法,该方法包括将对诱导式多能性干细胞进行分化诱导而获得的体细胞移植到该患者中的步骤,所述诱导式多能性干细胞是通过使用从患者中分离和采集的体细胞用上述方法获得的。
而且,本发明还提供了使用对由上述方法获得的诱导式多能性干细胞进行分化诱导而获得的各种细胞来评价化合物、药物、毒物等的生理作用和毒性的方法。
而且,本发明提供了一种改善细胞的分化能力和/或增殖能力的方法,该方法包括使上述的核重新编程因子与细胞接触的步骤,以及提供了由上述方法获得的细胞和对由上述方法获得的细胞进行分化诱导而得到的体细胞。
通过使用由本发明提供的核重新编程因子,不利用胚和ES细胞就可以简便且再现性强地诱导分化细胞核的重新编程,可以建立与ES细胞具有同样的分化和多能性和增殖能力的未分化细胞-诱导式多能性干细胞。例如、使用本发明的核重新编程因子能够由患者自身的体细胞制备具有高增殖能力和分化多能性的诱导式多能性干细胞,通过使该细胞分化而获得的细胞(例如心肌细胞、胰岛素产生细胞、或神经细胞等)可以应用于针对心力衰竭、胰岛素依赖性糖尿病、帕金森病和脊髓损伤等多种疾病的干细胞移植疗法中,由此可以回避使用人胚的伦理问题以及移植后的排斥反应,因此极为有用。而且,可以使诱导式多能性干细胞分化的各种细胞(例如心肌细胞、肝细胞等),作为用于评价化合物、药物、毒物等的药效和毒性的***极为有用。
附图简述
图1是表示使用在Fbx15基因中敲入了βgeo的小鼠的胎儿成纤维细胞(MEF)的重新编程因子的筛选方法的图。
图2是表示通过导入表1中所示的24个基因而获得的iPS细胞的形态的照片。还显示了分化细胞(MEF)和正常的胚胎干细胞(ES)的形态作为对照。
图3是表示iPS细胞中标记基因的表达的图。显示了以从iPS细胞、ES细胞和MEF细胞中提取的总RNA作为模板进行RT-PCR获得的结果。
图4是表示iPS细胞中DNA甲基化状态的图。对从iPS细胞、ES细胞、和MEF细胞提取的基因组DNA进行亚硫酸盐处理,对目的DNA进行PCR扩增后,***于质粒。每个基因分离出10个克隆的质粒,测定序列。甲基化CpG用黑点表示,非甲基化CpG用白点表示。
图5是表示通过24个基因的群、和从24个基因的群中每次除去1个基因后的23个基因的群的导入获得的G418细胞的克隆数的图。图下侧表示G418选择后一周内获得的集落数,图上侧表示3周内获得的集落数。当除去用四方形围起来的基因(基因的编号与表1所示的相同)时,完全没有获得集落,或是在3周后只发现少数集落。
图6是表示通过10个基因的群、和从10个基因的群中每次除去1个基因后的9个基因的群的导入而获得的G418细胞的集落数的图。除了#14、#15、或#20的各基因时一个集落都没有获得。当除去#22的基因时,获得了少数的G418抗性集落,但是细胞呈现出分化的形态,其明显与iPS细胞不同。
图7是表示由10个基因的群、4个基因的群、3个基因的群、或2个基因的群产生的G418抗性集落(重新编程集落)的出现数的图。显示了各集落的代表性形态及大小。
图8是表示对将MEF来源的iPS细胞移植到裸鼠皮下形成的肿瘤进行苏木精-曙红(H&E)染色的结果的照片。发现了三胚层系向各种组织的分化。
图9是表示通过将成体皮肤成纤维细胞来源的iPS细胞移植到小鼠胚泡中,移植到假孕小鼠的子宫中制备的胎儿的照片。由上图可知在左侧的胎儿中来源于iPS细胞的细胞(发出绿色荧光)分布于全身。在下图中清楚了同一胎儿的心脏、肝脏、脊髓的几乎全部细胞为GFP阳性,其源于iPS细胞。
图10是表示通过RT-PCR确认ES细胞标记基因的表达的结果的照片。图中,Sox2minus表示在MEF中导入3个基因而建立的iPS细胞,4ECAT表示在MEF中导入4个基因而建立的iPS细胞,10ECAT表示在MEF中导入10个基因而建立的iPS细胞,10ECAT皮肤成纤维细胞表示在皮肤成纤维细胞中导入10个基因而建立的iPS细胞,ES细胞表示小鼠ES细胞,MEF表示没有进行基因导入的MEF细胞。其下的编号表示克隆编号。
图11是表示在由MEF建立iPS细胞中bFGF的效果的图。在常规的饲养细胞(STO细胞)(左)和导入了bFGF表达载体的STO细胞(右)上培养的Fbx15βgeo/βgeo小鼠来源的MEF中通过逆转录病毒导入4个因子(上部分)或c-Myc以外的3个因子(下部分)。2周内通过G418进行选择,经晶体蓝染色后,拍照。数字表示集落数。
图12是对采用Nanog-EGFP-IRES-Puro小鼠的实验进行说明的图。A.分离在中心含有小鼠Nanog基因的大肠杆菌人工染色体(BAC),在Nanog的编码环形区域的上游通过重组***EGFP-IRES-Puro盒。B.用改良的BAC制备转基因小鼠。发现GFP的表达局限于胚泡的内细胞团块和生殖腺中。
图13是表示对使用Nanog-EGFP-IRES-Puro小鼠的实验进行说明的图。从Nanog-EGFP-IRES-Puro小鼠的胎儿(受精后13.5日)中除去头部、内脏和生殖腺,建立MEF。用细胞分选器进行分析的结果是,即使在Nanog-EGFP-IRES-Puro小鼠来源的MEF(Nanog)中,与Fbx15βgeo/βgeo小鼠来源的MEF(Fbx15)和野生型小鼠来源的MEF(Wild)同样,几乎不存在GFP阳性细胞。
图14是由Nanog-EGFP-IRES-Puro小鼠MEF(左)和Fbx15βgeo/βgeo小鼠MEF(右)建立的iPS细胞的照片。分别用嘌呤霉素和G418进行选择。
图15是表示iPS细胞的增殖的结果的图。表示将ES细胞、Nanog-EGFP-IRES-Puro小鼠MEF(左)来源的iPS细胞(Nanog iPS)和Fbx15βgeo/βgeo小鼠MEF来源的iPS细胞(Fbx iPS)各10万个分别接种于24孔板中,每3天进行一次传代,测定细胞数的结果。数字表示加倍时间的平均。
图16是表示iPS细胞的基因表达的图。用RT-PCR分析标记基因在MEF、ES细胞、Nanog-EGFP-IRES-Puro小鼠MEF(左)来源的iPS细胞(Nanog iPS)和Fbx15βgeo/βgeo小鼠MEF来源的iPS细胞(Fbx iPS)中的表达。下面的数字表示传代数。
图17是表示由Nanog iPS细胞形成畸胎瘤的图。显示在裸鼠的背部皮下注射100万个ES细胞或Nanog iPS细胞,3周后产生的肿瘤的外观(左)和组织图像(右:H&E染色)。
图18是表示用Nanog iPS细胞制备嵌合体小鼠的图。将Nanog iPS细胞(克隆NPMF4EK-24,传代数6)移植于胚泡中,诞生出嵌合体小鼠。由90个移植胚诞生出4只嵌合体小鼠。
图19是表示由Nanog iPS细胞出发的种系传递(germlinetransmission)的图。对通过图18所示的嵌合体小鼠与C57BL/6小鼠的交配所诞生的小鼠进行基因组DNA的PCR分析时,根据在所有的小鼠中存在Oct3/4和Klf4的转基因,确认了种系传递。
图20是表示由iPS细胞向神经细胞的分化诱导的图。显示由来源于皮肤成纤维细胞的iPS细胞在体外分化成的神经细胞(上:βIII微管蛋白阳性)、寡突胶质细胞(左:O4阳性)、星形胶质细胞(右:GFAP阳性)。
图21是表示对不使用药物选择的iPS细胞的建立进行说明的图。在每个10cm皿中接种1万至10万个MEF,通过逆转录病毒导入4个因子。对照(Mock)中没有产生集落(左),而导入了4个因子的皿中,除了扁平的转化集落,还获得了与膨胀的iPS细胞相类似的集落(中央)。一旦将这些细胞传代培养,就获得了与iPS细胞相类似的细胞(右)。
图22是表示通过无药物筛选建立的细胞的基因表达的图。从图21中所示的建立的细胞中提取RNA,用RT-PCR分析ES细胞标记基因的表达。
图23是表示人成纤维细胞来源的iPS细胞样细胞的图。显示了通过逆转录病毒将4个因子的人同源基因导入于人胎儿来源的成纤维细胞中而获得的集落(左)、和2次传代后的细胞(右)。
图24是表示由人成体皮肤成纤维细胞建立iPS细胞的图。通过逆转录病毒将左边部分所示的因子导入到用慢病毒感染了小鼠逆转录病毒受体的人成体皮肤成纤维细胞中。照片表示病毒感染后第8天的相位差图像(物镜x10)。
用于实施发明的最佳方式
本发明的核重新编程因子的特征在于含有下述3种基因:Oct家族基因、Klf家族基因和Myc家族基因的各基因的产物,在优选方式中,特征在于除了上述的3种基因之外还含有Sox家族基因的基因产物。
作为确认本发明的核重新编程因子的方法,可以利用例如、国际公开WO2005/80598中记载的核重新编程因子的筛选方法。通过参照上述出版物的所有公开的内容,包含于本说明书的公开内容中。本领域人员参照上述出版物筛选核重新编程因子,可以确认本发明的重新编程因子的存在和作用。
例如,可以利用Fbx15基因座中敲入了βgeo(β半乳糖苷酶和新霉素抗性基因的融合基因)的小鼠作为容易观察重新编程现象的实验***。详细内容示于本说明书的实施例中。小鼠Fbx15基因是在ES细胞和早期胚等的分化多能性细胞中特异性表达的基因。在小鼠Fbx15基因中敲入βgeo的且缺失Fbx15的功能的同源变异小鼠中,通常没有观察到包括分化多能性或发生在内的异常的表现型。在该小鼠中,βgeo受到Fbx15基因的增强子和启动子的表达控制,βgeo在分化的体细胞中不表达,显示出对G418的敏感性。另一方面,敲入了βgeo的同源变异ES细胞显示出对极高浓度(12mg/ml以上)的G418的抗性。利用该现象,可以构建使体细胞的重新编程可视化的实验***。
利用上述实验***,可以首先从敲入了βgeo的同源变异小鼠的胎儿(受精后13.5天)中分离成纤维细胞(Fbx15βgeo/βgeo的MEF)。由于MEF不表达Fbx15基因,因此也不表达βgeo,表现出对G418的敏感性。可是,一旦该MEF与没有进行基因操作的ES细胞(仍然呈现对G418的敏感性)相融合,MEF的核进行重新编程的结果是,表达βgeo而形成G418抗性。因此,通过利用该实验***,可以置换成G418抗性使重新编程现象可视化。
可以使用上述的实验***选择核重新编程因子。作为与核重新编程因子相关的基因的候选物,选择出多个显示出在ES细胞中特异性表达的基因和提示在ES细胞的分化多能性维持中起重要作用的基因,通过这些候选物单独或适当组合可以确认是否引出核重新编程。例如,通过组合所有的选择出的初次候选物,确认可以将分化细胞重新编程诱导至接近ES细胞的状态后、制备从前述组合中每次除去1个基因的组合,确认同样的作用,可以选择该基因不存在时重新编程诱导能力减弱,或重新编程诱导能力丧失的二次候选物。对于这样选择出的二次候选物,通过重复同样的步骤,可以选择出必需的核重新编程基因的组合,可以确认Oct家族基因、Klf家族基因和Myc家族基因的3种基因的基因产物的组合作为核重新编程因子起作用,除了这3种基因的基因产物,还可以确认Sox家族基因的基因产物的组合作为核重新编程因子具有极好的性质。核重新编程因子的选择方法的具体例子具体示于本说明书的实施例中,本领域技术人员参照上述的一般的说明和实施例的具体性说明可以容易地确认这3种基因的组合诱导体细胞的重新编程,和这3种基因产物的组合对于核重新编程是必需的。
由本发明提供的核重新编程因子至少含有Oct家族基因、Klf家族基因和Myc家族基因的基因产物的组合,包括例如Oct3/4、Klf4和c-Myc这3种基因的基因产物的组合。作为Oct家族基因,可以例举例如Oct3/4、Oct1A和Oct6等。Oct3/4是属于POU家族的转录因子,据报道其是未分化标记(K.Okamoto等,Cell,60,pp461-72,1990)。而且,还有报告指出Oct3/4与多能性维持相关(J.Nichols等,Cell,95,pp379-91,1998)。作为Klf家族基因,可以例举Klf1、Klf2、Klf4和Klf5等。据报道Klf4(Kruppel likefactor-4)是肿瘤抑制因子(A.M.Ghaleb等,Cell Res.,15,pp92-6,2005)。作为Myc家族基因,可以例举c-Myc、N-Myc和L-Myc等。有报道指出c-Myc是与细胞的分化和增殖相关的转录控制因子(S.Adhikary,M.Eilers,Nat.Rev.Mol.Cell Biol.,6,pp635-45,2005),且与多能性维持相关(P.Cartwright等,Development,132,pp885-96,2005)。Oct3/4、Klf4和c-Myc以外的各家族基因的NCBI登录号如下所示。
表1
小鼠 人
这些基因都是在包括人在内的哺乳类动物中共通存在的基因,为了在本发明中利用上述基因产物,可以使用任意哺乳类动物来源(例如小鼠、大鼠、牛、绵羊、马、猴等的哺乳类动物来源)的基因。而且,除了野生型的基因产物外,还可以利用取代、***和/或缺失了多个(例如1~10个、优选1~6个、更优选1~4个、更优选1~3个、特别优选1或2个)氨基酸的,且与野生型的基因产物具有同样功能的变异基因产物。例如,除了野生型之外还可以使用稳定型(T58A)等作为c-Myc的基因产物。对于其它的基因产物也是同样。
本发明的核重新编程因子,除了上述3种基因产物之外,可以包括其它的基因产物。作为这样的基因产物,可以例举Sox家族基因的基因产物。作为Sox家族基因,可以例举,例如Sox1、Sox3、Sox7、Sox15、Sox17、和Sox18、优选Sox2。至少包括Oct家族基因(例如Oct3/4)、Klf家族基因(例如Klf4)、Myc家族基因(例如c-Myc)和Sox家族基因(例如Sox2)这4种基因的基因产物的组合的核重新编程因子,从重新编程的效率的观点出发是本发明的优选方式,尤其是为了获得多能性,存在优选组合Sox家族基因的基因产物的情形。Sox2在初期发生过程中表达,是编码转录因子的基因(A.A.Avilion等,Genes Dev.,17,pp126-40,2003)。Sox2以外的Sox家族基因的NCBI登录号如下所示。
表2
小鼠 人
Sox1 | 含有SRY-盒的基因1 | NM_009233 | NM_005986 |
Sox3 | 含有SRY-盒的基因3 | NM_009237 | NM_005634 |
Sox7 | 含有SRY-盒的基因7 | NM_011446 | NM_031439 |
Sox15 | 含有SRY-盒的基因15 | NM_009235 | NM_006942 |
Sox17 | 含有SRY-盒的基因17 | NM_011441 | NM_022454 |
Sox18 | 含有SRY-盒的基因18 | NM_009236 | NM_018419 |
而且,Myc家族基因的基因产物存在可以被细胞因子替代的情况。作为细胞因子,例如,优选SCF或bFGF等,但不仅限于此。
作为更优选方式,除了上述3种基因产物、优选上述4种基因产物外,还可以列举诱导细胞的永生的因子。例如,可以列举包括TERT基因的基因产物的因子,与包括选自于下述基因中的1种以上的基因的基因产物的因子的组合:SV40大T抗原、HPV16E6、HPV16E7和Bmil。TERT是DNA复制时用于维持染色体末端端粒结构所必需的,在人中的干细胞和肿瘤细胞中表达,但是在许多体细胞中没有发现表达(I.Horikawa,等,Proc Natl Acad Sci USA.102,pp18437-442,2005)。据报道,SV40大T抗原、HPV16E6、HPV16E7或Bmil通过与大T抗原组合,导致人体细胞的永生(S.Akimov等,Stem Cells,23,pp1423-1433,2005;P.Salmon等,Mol.Ther.,2,pp404-414,2000)。这些因子,尤其是在由人细胞诱导iPS细胞时极为有用。TERT和Bmi1基因的NCBI登录号如下所示。
表3
小鼠 人
TERT | 端粒酶逆转录酶 | NM_009354 | NM_198253 |
Bmi1 | B淋巴瘤Mo-MLV***区域1 | NM_007552 | NM_005180 |
而且,还可以组合选自于下述基因中的1种或2种以上的基因的基因产物:Fbx15、Nanog、ERas、ECAT15-2、Tcl1和β-连环素。出于重新编程的效率的观点,作为特别优选的方式,可以例举含有将Fbx15、Nanog、ERas、ECAT15-2、Tcl1和β-连环素的基因产物与上述4种基因产物组合的共计10种基因产物的核重新编程因子。有报道指出Fbx15(Y.Tokuzawa等,Mol Cell Biol.,23,pp2699-708,2003)、Nanog(K.Mitsui等,Cell,113,pp631-42,2003)、ERas(K.Takahashi,K.Mitsui,S.Yamanaka,Nature,423,pp541-5,2003)和ECAT15-2(A.Bortvin等,Development,130,pp1673-80,2003)为ES细胞特异性表达基因,Tcl1与Akt的活性化相关(A.Bortvin等,Development,130,pp1673-80,2003)、β-连环素为Wnt信号传递途径的重要构成因子,与多能性维持相关(N.Sato等,Nat.Med.,10,pp55-63,2004)。
而且,本发明的核重新编程因子还可以含有例如、选自于选自于由下述的基因构成的组中的1种以上的基因的基因产物:ECAT1、Esg1、Dnmt3L、ECAT8、Gdf3、Sox15、ECAT15-1、Fthl17、Sall4、Rex1、UTF1、Stella、Stat3和Grb2。ECAT1、Esg1、ECAT8、Gdf3和ECAT15-1为ES细胞特异性表达基因(K.Mitsui等,Cell,113,pp631-42,2003)、Dnmt3L是DNA甲基化酶相关因子,Sox15是在初期发生过程中表达编码转录因子的一组基因(M.Maruyama等,J Biol Chem.,280,pp24371-9,2005)。Fthl17编码铁蛋白重链多肽-样17(A.colLoriot,T.Boon,C.De Smet,Int J Cancer,105,pp371-6,2003),Sall4编码在胚胎干细胞中高表达的锌指蛋白质(J.Kohlhase等,Cytogenet Genome Res.,98,pp274-7,2002)、Rex1编码存在于Oct3/4下游的转录因子(E.Ben-Shushan,J.R.Thompson,L.J.Gudas,Y.Bergman,Mol Cell Biol.,18,pp1866-78,1998)。有报道指出UTF1是位于Oct3/4下游的转录辅助因子,一旦抑制它就抑制ES细胞的增殖(A.Okuda等,EMBO J.,17,pp2019-32,1998)。Stat3是细胞增殖·分化的信号因子,通过Stat3的活性化,激起LIF的运作,对多能性维持起重要的作用(H.Niwa,T.Burdon,I.Chambers,A.Smith,Genes Dev.,12,pp2048-60,1998)。Grb2编码存在于细胞膜的各种成长因子受体和Ras/MAPK级联之间进行介导的蛋白质(A.M.Cheng等,Cell,95,pp793-803,1998)。
不过,可以包含于本发明的核重新编程因子的基因产物不限于上述具体说明的基因的基因产物。本发明的核重新编程因子中,除了可以作为核重新编程因子起功能的其它基因产物之外,还可以包括1或2种以上的与分化、发生或增殖等相关的因子或具有其它生理活性的因子,当然这样的实施方式也应理解为包含于本发明的范围中。可以作为核重新编程因子起作用的其它基因产物,可以使用例如、只使Oct3/4、Klf4和c-Myc这3种基因中的1种或2种表达的体细胞,通过筛选可以诱导该细胞的核重新编程的基因产物进行鉴定。通过本发明提供了上述筛选方法作为新的核重新编程因子的筛选方法。
而且,包含于本发明的核重新编程因子的基因产物除了例如由上述基因产生的蛋白质自身之外,还可以是该蛋白质与其它的蛋白质或肽等的融合基因产物的形态。例如,还可以使用与绿色荧光蛋白质(GFP)的融合蛋白质或与组氨酸标签等肽的融合基因产物。而且,制备与来源于HIV病毒的TAT肽的融合蛋白质,通过使用该融合蛋白质,可以促进细胞膜对于核重新编程因子的细胞内摄取,可以回避基因导入等复杂的操作,只在培养基中添加融合蛋白质就可以诱导重新编程。这种融合基因产物的制备方法是本领域技术人员所熟知的,因此本领域技术人员根据目的,可以容易地设计适当的融合基因产物并进行制备。
使用本发明的核重新编程因子,使体细胞的核重新编程,可以获得诱导式多能性干细胞。本说明书中所谓“诱导式多能性干细胞”是具有接近于ES细胞的性质的细胞,更具体的是,包含一种未分化的且具有多能性和增殖能力的细胞,但该用语无论在何种意思中都不是限定性解释,需要最广义的解释。对于使用核重新编程因子制备诱导式多能性干细胞的方法,在国际公开WO2005/80598中已有说明(上述公报中使用了ES样细胞这样的用语)、诱导式多能性干细胞的分离方法也有具体的说明。因此,本领域技术人员通过参照上述出版物,可以使用本发明的核重新编程因子容易地制备诱导式多能性干细胞。
对使用本发明的核重新编程因子由体细胞制备诱导式多能性干细胞的方法没有特别的限定,如果在体细胞和诱导式多能性干细胞可以增殖的环境中核重新编程因子可以与体细胞接触,可以采用任意一种方法。例如,可以在培养基中添加包含于本发明的核重新编程因子中的基因产物,或还可以采用使用含有可以表达本发明的核重新编程因子的基因的载体将该基因导入体细胞中等方法。使用这种载体时,通过在载体中整合2种以上的基因,也可以使各个基因产物在体细胞中同时表达。在应当重新编程的体细胞中,包含于本发明的核重新编程因子中的基因产物中的1种或2种以上已经表达时,可以从本发明的核重新编程因子中除去该基因产物,这样的实施方式也应理解为包含于本发明的范围中。
使用本发明的核重新编程因子制备诱导式多能性干细胞时,对应当重新编程的体细胞的种类没有特别的限定,可以使用任意的体细胞。例如、除了胎儿期的体细胞之外,也可以使用成熟的体细胞。在疾病的治疗中使用诱导式多能性干细胞时,理想的是使用从患者中分离的体细胞,例如,可以使用与疾病相关的体细胞或与疾病治疗相关的体细胞等。对按照本发明的方法选择在培养基中出现的诱导式多能性干细胞的方法没有特别的限定,例如,可以适当采用使用药物抗性基因等作为标记基因,以药物抗性作为指标分离诱导式多能性干细胞等的公知的方法。可以维持ES细胞的未分化性和多能性的培养基或不能维持该性质的培养基在本领域中已知有多种,通过组合使用适当的培养基,可以有效分离诱导式多能性干细胞。通过利用对于ES细胞广泛使用的确认手段,本领域技术人员可以容易地确认分离的诱导式多能性干细胞的分化能力和增殖能力。
对用本发明的方法制备的诱导式多能性干细胞的用途没有特别的限定,可以在使用ES细胞进行的所有的试验·研究和使用ES细胞的疾病的治疗等中进行利用。例如,通过用视黄酸、EGF等增殖因子、或糖皮质激素等处理由本发明的方法获得的诱导式多能性干细胞,可以诱导所希望的分化细胞(例如神经细胞、心肌细胞、血细胞等),通过将这样获得的分化细胞返回到患者中的自身细胞移植可实现干细胞疗法。然而,本发明的诱导式多能性干细胞的用途不限于上述的特定的方式。
实施例
以下,通过实施例对本发明进行更具体的说明,但本发明的范围不受下述实施例的限定。
例1:重新编程因子的选择
为了鉴定重新编程因子,需要容易地观察重新编程现象的实验***。作为实验***,利用在Fbx15基因座中敲入了βgeo(β半乳糖苷酶和新霉素抗性基因的融合基因)的小鼠。小鼠Fbx15基因是在ES细胞和初期胚等分化多能性细胞中特异性表达的基因。然而,在小鼠Fbx15基因中敲入了βgeo的、缺失Fbx15功能的同源变异小鼠中没有观察到包括分化多能性和发生在内的异常的表现型。在该小鼠中,βgeo受到Fbx15基因的增强子和启动子的表达控制。也就是,βgeo在分化的体细胞中不表达,对G418显示出敏感性。一方面,敲入了βgeo的同源变异ES细胞对极高浓度(12mg/ml以上)的G418显示出抗性。利用该现象,构建使体细胞的重新编程可视化的实验***。
上述实验***中,首先从敲入了βgeo的同源变异小鼠的胎儿(受精后13.5日)中分离成纤维细胞(Fbx15βgeo/βgeo的MEF)。由于MEF不表达Fbx15基因,因此也不表达βgeo,对G418显示出敏感性。另一方面,一旦该MEF与不进行基因操作的ES细胞(仍然呈现对G418的敏感性)相融合,MEF的核进行重新编程的结果是,表达βgeo而形成G418抗性。也就是,通过该实验***,可以使重新编程现象可视化为G418抗性(国际公开WO2005/80598)。使用上述实验***进行重新编程因子的探索(图1),选择出在ES细胞中显示特异性表达的基因、和提示在ES细胞的分化多能性维持中有重要作用的基因共计24种作为重新编程因子的候选物。这些基因示于下表4和表5中。而且,就#21的β-连环素和#22的c-Myc而言,使用了活性型的变异体(连环素:S33Y,c-Myc:T58A)。
表4
编号 | 基因名 | 基因的说明 |
1 | ECAT1 | ES细胞相关转录物1(ECAT1) |
2 | ECAT2 | 发育多潜能性相关5(DPPA5),ES细胞特异性基因1(ESG1) |
3 | ECAT3 | F-box蛋白质15(Fbx15), |
4 | ECAT4 | 同源框(homeobox)转录因子Nanog |
5 | ECAT5 | ES细胞表达的Ras(ERas), |
6 | ECAT7 | DNA(胞嘧啶-5-)-甲基转移酶3-样(Dnmt3l),变异体(valiant)1 |
7 | ECAT8 | ES细胞相关转录物8(ECAT8) |
8 | ECAT9 | 生长分化因子3(Gdf3), |
9 | ECAT10 | 含有SRY-盒的基因15(Sox15), |
10 | ECAT15-1 | 发育多潜能性相关4(Dppa4),变异体1 |
11 | ECAT15-2 | 发育多潜能性相关2(Dppa2), |
12 | Fthl17 | 铁蛋白,重链多肽-样17(Fthl17), |
13 | Sall4 | sal-样4(果蝇)(Sall4),转录物变异体a |
表4(续)
14 | Oct3/4 | POU域,类5,转录因子1(Pou5f1), |
15 | Sox2 | 含有SRY-盒的基因2(Sox2), |
16 | Rex1 | 锌指蛋白42(Zfp42), |
17 | Utf1 | 未分化的胚胎细胞转录因子1(Utf1) |
18 | Tcl1 | T-细胞淋巴瘤断点1(Tcl1), |
19 | Stella | 发育多潜能性相关3(Dppa3), |
20 | Klf4 | Kruppel-样因子4(gut)(Klf4), |
21 | β-Catenin | 连环素(钙粘蛋白相关蛋白),β1,88kDa(Ctnnb1) |
22 | c-Myc | 髓细胞增生癌基因(Myc), |
23 | Stat3 | 信号转导子和转录激活子3(Stat3),转录物变异体1 |
24 | Grb2 | 生长因子受体结合蛋白2(Grb2), |
表5
NCBI登录号
表5(续)
表5(续)
在逆转录病毒载体pMX-gw中通过Gateway技术***这些基因的cDNA。首先使24个基因一个一个地感染Fbx15βgeo/βgeo的MEF,然后,在ES细胞培养条件下进行G418选择。然而,G418抗性集落一个都没有获得。接着,使所有24个基因的逆转录病毒同时感染Fbx15βgeo/βgeo的MEF。在ES细胞培养条件下进行G418选择时,获得了多个药物抗性集落。分离这些集落继续培养。这些细胞可以长期培养,而且清楚地显示出与ES细胞类似的形态(图2)。图中,iPS细胞表示诱导式多能性干细胞(也称为ES样细胞、ES-like细胞、ESL细胞),ES表示胚胎干细胞,MEF表示分化细胞(胎儿成纤维细胞)。
通过RT-PCR研究标记基因的表达,Nanog、Oct3/4等的未分化标记表达了(图3)。清楚了Nanog的表达接近于ES细胞,但Oct3/4的表达比ES细胞低。而且,通过亚硫酸盐测序法确认了DNA甲基化状态,清楚了Nanog基因和Fbx15基因在MEF中处于高甲基化状态,但在iPS细胞中被脱甲基化(图4)。印记(imprinting)基因-IGF2基因在MEF和iPS细胞这两者中约50%被甲基化。已知收集了Fbx15βgeo/βgeo的MEF,受精后13.5天的原始生殖细胞中失去印记记忆的IGF2基因几乎被完全脱甲基化,因此得出了iPS细胞不是来源于混入Fbx15βgeo/ βgeo的MEF中的原始生殖细胞的结论。根据以上结果,表示通过24种因子的组合,可以将分化细胞(MEF)重新编程诱导成接近于ES细胞的状态。
然后,对所有24种基因对于重新编程是否必需进行了研究。使每次除去1个基因的23个基因感染Fbx15βgeo/βgeo的MEF。其结果清楚了,对于10个基因,除去它们的时候,抑制集落的形成(图5:基因的编号对应于表4中所示的基因的编号,#3、#4、#5、#11、#14、#15、#18、#20、#21、和#22这10种基因)。使这10种基因同时感染Fbx15βgeo/ βgeo的MEF时,结果,与使24种基因同时感染时相比,显著更有效地获得了G418抗性集落。
进而,使这10个基因中每次除去1个基因的9个基因感染Fbx15βgeo/βgeo的MEF。其结果是,发现分别除去4种基因(#14、#15、#20、或#22)时,没形成G418抗性的iPS细胞集落(图6)。因此提示,10个基因中,这4种基因对于重新编程诱导来说起到了特别重要的作用。
例2:通过4种基因群的组合进行的重新编程诱导
对10种基因中提示有特别重要性的4个基因是否可以诱导体细胞的重新编程进行了研究。在Fbx15基因中敲入了βgeo的MEF的细胞中,使用上述10种基因的组合、上述4种基因的组合、上述4种中的仅3种基因的组合和上述4种中的仅两种基因的组合,将这些基因组合(gene set)通过逆转录病毒导入体细胞中。其结果是在导入了4种基因时获得了160个G418抗性集落。尽管该结果与导入10种基因时的结果(179个集落)几乎数量相同,但是导入4个基因时,集落比导入10个基因时要小。而且,传代培养这些集落时,呈现iPS细胞的形态的集落,在导入10个基因时,在12个克隆中有9个克隆,与之相对,在导入4个基因时,12个克隆中有7个克隆,存在某种程度减少的倾向。作为4个基因,无论是小鼠来源的基因还是人来源的基因中都获得了数目几乎相同的iPS细胞。
导入从上述4个基因中选择出的3个基因时,有个组合(#14、#15和#20)中获得了36个扁平的集落,但是即使传代培养也没有观察到iPS细胞。其它的组合(#14、#20、和#22)中获得了54个小集落。这些集落中,对较大的6个集落进行次传代培养时,所有6个克隆都获得了与ES细胞类似的细胞。然而,如果与ES细胞相比,认为细胞与细胞之间以及与培养皿的粘附弱。而且,细胞增殖的速度,与导入4个基因的情况相比要慢。而且,从4个基因中选择出3个基因的其它的2组组合中分别形成了各1个集落,但是即使传代培养也没有发现细胞的增殖。从4个基因中选择出的2个基因的组合(组合6)中,每一种情况连1个G418抗性集落都没有形成。以上结果示于图7。
而且,图10中,表示了通过RT-PCR确认ES细胞标记基因的表达的结果。方法的详细内容如下所示。从向Fbx15βgeo/βgeo的MEF中导入3个基因(Oct3/4、Klf4和c-Myc、表示为Sox2minus)、4个基因(除3个基因之外还加上了Sox2,表示为4ECAT)、10个基因(除了4个基因之外还加上了表1的#3、#4、#5、#11、#18、#21,表示为10ECAT)所建立的iPS细胞、在有其Fbx15基因中敲入了βgeo的成体小鼠的尾部皮肤而建立的成纤维细胞中导入10个基因所建立的iPS细胞(表示为10ECAT皮肤成纤维细胞)、从小鼠ES细胞和没有导入基因的MEF细胞中纯化总RNA,通过DNaseI处理除去混入的基因组DNA。通过逆转录反应制备第一链cDNA,通过PCR研究ES细胞标记基因的表达。而且,对于Oct3/4、Nanog、ERas,使用不对来自导入的逆转录病毒,而只对来自内源性基因扩增转录产物的引物进行PCR。引物序列示于表6。
表6
ECAT1 | ECAT1-RT-S | TGT GGG GCC CTG AAA GGC GAG CTG AGA T |
ECAT1-RT-AS | ATG GGC CGC CAT ACG ACG ACG CTC AAC T | |
Esg1 | pH34-U38 | GAA GTC TGG TTC CTT GGC AGG ATG |
pH34-L394 | ACT CGA TAC ACT GGC CTA GC | |
Nanog | 6047-S1 | CAG GTG TTT GAG GGT AGC TC |
6047-AS1 | CGG TTC ATC ATG GTA CAG TC | |
ERas | 45328-S118 | ACT GCC CCT CAT CAG ACT GCT ACT |
ERas-AS304 | CAC TGC CTT GTA CTC GGG TAG CTG | |
Gdf3 | Gdf3-U253 | GTT CCA ACC TGT GCC TCG CGT CTT |
GDF3L16914 | AGC GAG GCA TGG AGA GAG CGG AGC AG | |
Fgf4 | Fgf4-RT-S | CGT GGT GAG CAT CTT CGG AGT GG |
Fgf4-RT-AS | CCT TCT TGG TCC GCC CGT TCT TA | |
Cripto | Cripto-S | ATG GAC GCA ACT GTG AAC ATG ATG TTC GCA |
Cripto-AS | CTT TGA GGT CCT GGT CCA TCA CGT GAC CAT | |
Zfp296 | Zfp296-S67 | CCA TTA GGG GCC ATC ATC GCT TTC |
Zfp296-AS350 | CAC TGC TCA CTG GAG GGG GCT TGC | |
Dax1 | Dax1-S1096 | TGC TGC GGT CCA GGC CAT CAA GAG |
Dax1-AS1305 | GGG CAC TGT TCA GTT CAG CGG ATC | |
Oct3/4 | Oct3/4-S9 | TCT TTC CAC CAG GCC CCC GGC TC |
Oct3/4-AS210 | TGC GGG CGG ACA TGG GGA GAT CC | |
NAT1 | NAT1U283 | ATT CTT CGT TGT CAA GCC GCC AAA GTG GAG |
NAT1L476 | AGT TGT TTG CTG CGG AGT TGT CAT CTC GTC |
根据此图中所示的结果,清楚了导入3个基因时,ERas和Fgf4被有效诱导表达,但不引起多能性维持所必需的因子-Oct3/4与Nanog的诱导,或者即使引起也非常弱。另一方面,导入4个基因时,在检测的4个克隆中,存在有一个Oct3/4和Nanog被较强诱导的克隆(#7)。进而,在导入10个基因时,研究的5个克隆中,3个克隆中发现了Oct3/4和Nanog的强诱导。
根据这些结果清楚了,为了重新编程,至少3个基因的组合(#14、#20、和#22)是必需的,在含有这3种基因的4个基因群和10个基因群中随着基因的数目增加,重新编程的效率上升。
例3:重新编程的细胞的多分化能力的分析
为了评价建立的iPS细胞的分化多能性,将通过24个因子、10个因子和4个因子建立的iPS细胞移植到裸鼠的皮下。其结果是,在所有例子中均形成了与ES细胞同样大小的肿瘤。以组织学观察,肿块由多种细胞构成,确认有软骨组织、神经组织、肌肉组织、脂肪组织和肠道样组织(图8),因此证明了iPS细胞的多能性。另一方面,一旦将由3个因子建立的细胞移植到裸鼠中就形成肿瘤,其只由组织学上未分化细胞形成。因而清楚了,为了诱导分化多能性,Sox家族是必需的。
例4:源于成体小鼠的尾部的成纤维细胞的重新编程
将用小鼠胎儿成纤维细胞(MEF)鉴定的4个因子导入来源在Fbx15基因中敲入βgeo且在全身表达绿色荧光蛋白质(GFP)的成体小鼠的尾部的成纤维细胞。然后,在饲养细胞上,在与ES细胞培养条件相同的条件下进行培养,通过G418进行选择。药物选择开始后约2周内获得了多个iPS细胞集落。一旦将这些细胞移植到裸鼠的皮下,就形成了三胚层系的各种组织构成的畸胎瘤。而且,将来源于成体皮肤成纤维细胞的iPS细胞移植到胚泡中,移植到假孕小鼠的子宫中,结果在受精后第13.5天的胚中发现GFP阳性细胞分布于全身(图9)。这表明iPS细胞具有多能性,对小鼠胚胎形成有作用。该结果表明鉴定的因子群不止对胎儿期的体细胞而且对成熟的小鼠的体细胞都具有诱导重新编程的能力。在成体皮肤来源的细胞中可以重新编程诱导这一点在实用性上极为重要。
例5
研究iPS细胞建立中细胞因子的影响。在饲养细胞(STO细胞)中导入碱性成纤维细胞生长因子(bFGF)或干细胞因子(SCF)的表达载体(pMX逆转录病毒载体),建立稳定表达这些细胞因子的细胞。在这些STO细胞上培养Fbx15βgeo/βgeo小鼠来源的MEF(50万个/100mm皿),导入4个因子后,通过G418进行选择时,结果与在常规的STO细胞上的培养的情况相比,在产生bFGF(图11)、SCF(数据未显示)的STO细胞上的集落形成数提高20倍以上。而且,即使导c-Myc以外的3个因子,在常规的STO细胞上没有形成iPS细胞集落,但是在产生bFGF(图11)、SCF(数据未显示)的STO细胞上发现集落的形成。根据这些结果,清楚了通过细胞因子的刺激,由MEF建立iPS细胞的效率提高,和可以通过使用细胞因子代替从c-Myc使核重新编程成为可能。
例6
Oct3/4、Klf4、c-Myc、和Sox2基因都存在家族基因(表1和2)。于是,研究通过家族基因代替4个基因是否可以建立iPS细胞。表7中公开了2次实验的汇总的结果。对于Sox家族而言,Sox1的G418抗性集落数和iPS细胞建立效率,均与Sox2的程度相同。Sox3的G418抗性集落数是Sox2的十分之一左右,但挑选的集落中的iPS细胞建立效率要比Sox2高。Sox15的G418抗性集落数和iPS细胞建立效率都比Sox2低。Sox17的G418抗性集落与Sox2程度相同,但是iPS细胞建立效率低。对于Klf家族而言,Klf2产生了比Klf4更少的G418抗性集落,iPS细胞的建立效率程度相同。对于Myc家族而言,首先确认了野生型的c-Myc与T58A变异体在G418抗性集落数、iPS细胞建立效率两方面的程度均相同。而且,N-Myc和L-Myc(都是野生型),同时在这二者中的c-Myc和G418抗性集落数、iPS细胞建立效率的程度均相同。
表7
例7
用Fbx15-βgeo以外的报告因子研究是否可以建立iPS细胞。首先,分离中心部位含有Nanog基因的大肠杆菌人工染色体(BAC),通过大肠杆菌内的重组,敲入GFP基因和嘌呤霉素抗性基因(图12A)。然后,在ES细胞中导入进行了相同的改良的BAC,确认了形成未分化状态特异的GFP阳性(数据未显示)。然后,通过移植到相同的ES细胞的小鼠胚泡中通过嵌合体小鼠制备转基因小鼠。在该小鼠中在胚泡的内部细胞块和受精后第13.5天胚的生殖腺中特异性发现了GFP阳性细胞(图12B)。从受精后13.5天胚(DBA、129和C57BL/6小鼠的杂种)中除去生殖腺,分离MEF。确认了用流式细胞仪分离的MEF为GFP阴性(图13)。通过逆转录病毒将4个因子导入于该MEF中,通过嘌呤霉素进行选择时,获得了多个抗性集落。其中只有约10~20%为GFP阳性。一旦传代培养GFP阳性集落,就呈现出类似于ES细胞的形态(图14)和增殖(图15)。而且如果观察基因表达,就会清楚相较于通过G418从Fbx15βgeo/βgeo的MEF中选择分离出的iPS细胞,其更接近于ES细胞的表达模式(图16)。一旦将该细胞移植于裸鼠中,根据形成畸胎瘤,确认了其为iPS细胞(图17)。而且,通过将经Nanog-GFP选择获得的iPS细胞移植到C57BL/6小鼠的胚泡中诞生了嵌合体小鼠(图18)。而且,通过使该嵌合体小鼠之间交配,确认了种系传递(图19)。在通过这种Nanog-GFP选择建立的更接近于ES细胞的iPS细胞中,来自于逆转录病毒的4个因子的表达几乎完全被沉默,这提示自我复制由于内源性的Oct3/4和Sox2而被维持。
例8
对10cm汇合的iPS细胞进行胰蛋白酶处理,悬浮于ES细胞用培养基中(悬浮后10~20分钟通过使STO细胞粘附于涂覆了明胶的皿,而将其除去)。在涂覆了HEMA(甲基丙烯酸-2-羟乙酯)的大肠杆菌培养用皿中悬浮培养2×106的细胞4天,使之形成胚状体(EB)(1-4天)。EB形成的第4天(第4天),将所有EB转移到10cm组织培养用皿中,用ES细胞用培养基培养24小时使之粘附。24小时后(第5天),更换成含有ITS/纤连蛋白的培养基。培养7天(每两天进行培养基更换)、选择脑巢蛋白(nestin)阳性细胞(如果在无血清下培养,其它谱系的细胞会在一定程度死亡)(第5-12天)。然后进行A2B5阳性细胞的诱导。7天后(第12天)通过胰蛋白酶处理使细胞分散,除去残存的EB。将1×105个细胞接种于涂覆了聚-L-鸟氨酸/纤连蛋白的24孔板上,在含有N2/bFGF的培养基中培养四天(每两天更换一次培养基(第12-16天)。四天后(第16天)更换成含有N2/bFGF/EGF的培养基,培养四天(每两天更换一次培养基)(第16-20天)。四天后(第20天)更换成含有N2/bFGF/PDGF的培养基,培养四天(每两天更换一次培养基)(第20-24天)。这期间(第12-24天),在细胞过度增加形成汇合的时候随时传代,接种1~2×105个细胞(数量由于传代时期而改变)。四天后(第24天)更换成N2/T3培养基,培养7天(第24-31天),每两天更换一次培养基。第31天固定,免疫染色。其结果是,确认了由iPS细胞分化出βIII微管蛋白阳性的神经细胞、O4阳性的寡突胶质细胞、GFAP阳性的星形胶质细胞(图20)。
例9
为了由敲入了Fbx15-βgeo的小鼠以外的任意的小鼠体细胞建立iPS细胞,开发了不使用药物选择的建立方法。在10cm皿(STO饲养细胞上)中培养比以上的更少数量(1万、5万或10万个)的小鼠胎儿成纤维细胞(MEF),通过逆转录病毒导入对照DNA或4个因子。在ES细胞培养基中进行2周培养(无G418选择),在导入了对照DNA的皿中没有发现集落形成,但在导入了4个因子的皿中除了被认为是转化的扁平的集落,还形成了多个致密的集落(图21)。从这些中选择出24个集落,继续培养,发现了ES细胞样的形态。通过RT-PCR研究其基因表达,7个克隆中发现了ES细胞标记-Esg1的表达。而克隆4中发现了Nanog、ERas、GDF3、Oct3/4、Sox2等许多ES细胞标记的诱导,因此被认为其是iPS细胞(图22)。根据以上结果,表明iPS细胞建立中使用Fbx15-βgeo敲入等的药物选择不是必需的,由任意的小鼠来源的体细胞可以建立iPS细胞。提示出通过本技术可以由疾病模型小鼠的体细胞中建立iPS细胞的可能性。
例10
作为诱导iPS细胞的细胞,研究了成纤维细胞以外的细胞-肝细胞和胃粘膜细胞。通过灌流从Fbx15βgeo/βgeo小鼠的肝脏中分离出肝细胞。用逆转录病毒将4个因子施加给该肝细胞,通过G418进行选择,结果获得了多个iPS细胞集落。通过DNA微阵列对基因表达模式进行分析的结果是,清楚了肝脏来源的iPS细胞比皮肤成纤维细胞和胎儿成纤维细胞来源的iPS细胞更接近于ES细胞。同样,从胃粘膜细胞和肝细胞中也获得了iPS细胞。
例11
已知PD98059为MAP激酶的抑制剂,在许多分化细胞中抑制增殖,但在ES细胞中促进未分化状态维持和增殖。于是研究了iPS细胞建立中PD98059的效果。用逆转录病毒将4个因子施加到由具有Nanog-EGFP-IRES-Puro的选择标记的小鼠建立的MEF中,通过嘌呤霉素进行选择。不施加PD98059时,在获得的iPS细胞集落中,GFP阳性的比率为8%。另一方面,逆转录病毒感染的次日开始持续施加PD98059(终浓度25μM)的组中,所获得的集落中的45%为GFP阳性。这可被认为因为PD98059促进GFP阳性的更接近ES细胞的iPS细胞的增殖,也可能是PD98059抑制GFP阴性的iPS细胞和分化细胞的增殖。因此表明PD98059可以用于更接近于ES细胞的iPS细胞的建立和不使用药物选择的iPS细胞的建立中。
例12
通过核转染(Nucleofection)将小鼠Oct3/4基因启动子下游整合了红色荧光蛋白质基因和在PGK启动子下游整合了潮霉素抗性基因的质粒导入于用慢病毒使小鼠同向性病毒(ecotropic virus)受体-可溶性载体家族7(Slc7a1、NCBI登录号NM_007513)在胎儿来源的人皮肤成纤维细胞(HDF)中表达的细胞中。通过潮霉素进行选择,建立稳定表达株。用丝裂霉素处理800000个的细胞,接种在STO细胞上,次日通过逆转录病毒导入Oct3/4、Sox2、Klf4、c-Myc(均来源于人)。挑选3周后获得的集落中的24个(图23左),转移到接种了STO细胞的24-孔板上进行培养。将2周后逐渐增加的1个克隆传代到接种了STO细胞的6-孔板上进行培养,结果获得了在形态上类似于ES细胞的细胞(图23右),提示其为iPS细胞。培养基通常使用小鼠ES细胞用培养基。
例13
将用慢病毒使Slc7a1(小鼠逆转录病毒受体)导入于人成体皮肤成纤维细胞(成体HDF)的细胞接种于800000个饲养细胞(丝裂霉素处理STO细胞)上,以以下组合,用逆转录病毒导入基因。
1.Oct3/4、Sox2、Klf4、c-Myc、TERT、SV40大T抗原
2.Oct3/4、Sox2、Klf4、c-Myc、TERT、HPV16E6
3.Oct3/4、Sox2、Klf4、c-Myc、TERT、HPV16E7
4.Oct3/4、Sox2、Klf4、c-Myc、TERT、HPV16E6、HPV16E7
5.Oct3/4、Sox2、Klf4、c-Myc、TERT、Bmi1
(Oct3/4、Sox2,Klf4,c-Myc,TERT来源于人,Bmi1来源于小鼠)
在小鼠ES细胞的培养条件下,继续无药物筛选的培养,在导入了组合1的因子的皿中,在病毒感染8天后出现了被认为是iPS细胞的集落(图24)。在其它的组合(2至5)中,尽管没有组合1的情况明显,但出现了iPS细胞样的集落。当只导入4个因子时,也没有出现任何集落。
产业上应用的可能性
通过使用由本发明提供的核重新编程因子,不使用胚和ES细胞就可以简便且再现性强地诱导分化细胞核的重新编程,可以建立与ES细胞具有同样的分化和多能性和增殖能力的未分化细胞-诱导式多能性干细胞。
本申请还包括下述内容:
1.一种体细胞的核重新编程因子,该因子含有下述3种基因:Oct家族基因、Klf家族基因和Myc家族基因的各基因的产物。
2.项1中记载的因子,其含有下述3种基因:Oct3/4、Klf4和c-Myc的各基因的产物。
3.项1或2中记载的因子,其还含有下述基因:Sox家族基因的基因产物。
4.项3中记载的因子,其含有Sox2的基因产物。
5.项1至4中任意一项中记载的因子,其含有细胞因子,该细胞因子和Myc家族基因的基因产物共同存在、或者代替Myc家族基因的基因产物。
6.项5中记载的因子,所述细胞因子为bFGF和/或SCF。
7.项1至6任意一项中记载的因子,其还含有下述的基因:TERT基因的基因产物。
8.项1至7任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因的基因产物:SV40大T抗原、HPV16E6、HPV16E7和Bmil。
9.项1至8任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因的基因产物:Fbx15、Nanog、ERas、ECAT15-2、Tcl1和β-连环素。
10.项1至9任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因的基因产物:ECAT1、Esg1、Dnmt3L、ECAT8、Gdf3、Sox15、ECAT15-1、Fthl17、Sall4、Rex1、UTF1、Stella、Stat3、和Grb2。
11.通过体细胞的核重新编程制备诱导式多能性干细胞的方法,其包括使项1至10任意一项中记载的核重新编程因子与该体细胞接触的步骤。
12.项11中记载的方法,所述体细胞为人细胞。
13.由项11或12中记载的方法获得的诱导式多能性干细胞。
14.通过诱导项13中记载的诱导式多能性干细胞分化而得到的体细胞。
15.一种改善细胞的分化能力和/或增殖能力的方法,该方法包括使项1至10任意一项中记载的核重新编程因子与细胞接触的步骤。
16.项15中记载的方法,所述细胞为人细胞。
17.由项15或16中记载的方法获得的细胞。
18.通过诱导项17中记载的细胞分化而得到的体细胞。
Claims (14)
1.一种体细胞的核重新编程因子,其含有下述3种基因:Oct3/4基因、Klf家族基因和Myc家族基因,其中的Klf家族基因选自Klf2基因或Klf4基因,Myc家族基因选自c-Myc基因、N-Myc基因、L-Myc基因和T58A基因。
2.权利要求1中记载的因子,其含有下述3种基因:Oct3/4、Klf4和c-Myc。
3.权利要求1记载的因子,其还含有Sox家族基因,所述Sox家族基因选自Sox1基因、Sox2基因、Sox3基因、Sox15基因以及Sox17基因。
4.权利要求3中记载的因子,其含有下述基因:Sox2基因。
5.权利要求3中记载的因子,其含有下述4种基因:Oct3/4、Klf4、c-Myc和Sox2。
6.权利要求3中记载的因子,其含有细胞因子,该细胞因子和Myc家族基因共同存在、或者代替Myc家族基因,所述细胞因子为bFGF和/或SCF。
7.权利要求1至6任意一项中记载的因子,其还含有TERT基因。
8.权利要求1至6任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因:SV40大T抗原、HPV16E6、HPV16E7和Bmil。
9.权利要求1至6任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因:Fbx15、Nanog、ERas、ECAT15-2、Tcl1和β-连环素。
10.权利要求1至6任意一项中记载的因子,其还含有选自于由下述的基因构成的组中的1种以上的基因:ECAT1、Esg1、Dnmt3L、EAT8、Gdf3、Sox15、ECAT15-1、Fthl17、Sall4、Rex1、UTF1、Stella、Stat3、和Grb2。
11.通过体细胞的核重新编程制备诱导式多能性干细胞的方法,其包括在体外使权利要求1至10任意一项中记载的核重新编程因子与该体细胞接触的步骤。
12.权利要求11中记载的方法,所述体细胞为人细胞。
13.一种改善细胞的分化能力和/或增殖能力的方法,该方法包括在体外使权利要求1至10任意一项中记载的核重新编程因子与细胞接触的步骤。
14.权利要求13中记载的方法,所述细胞为人细胞。
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US9012219B2 (en) * | 2005-08-23 | 2015-04-21 | The Trustees Of The University Of Pennsylvania | RNA preparations comprising purified modified RNA for reprogramming cells |
ES2698600T3 (es) | 2005-12-13 | 2019-02-05 | Univ Pennsylvania | Métodos para transfectar ácidos nucleicos en células vivas |
US8278104B2 (en) * | 2005-12-13 | 2012-10-02 | Kyoto University | Induced pluripotent stem cells produced with Oct3/4, Klf4 and Sox2 |
US20090227032A1 (en) * | 2005-12-13 | 2009-09-10 | Kyoto University | Nuclear reprogramming factor and induced pluripotent stem cells |
US10647960B2 (en) * | 2005-12-13 | 2020-05-12 | The Trustees Of The University Of Pennsylvania | Transcriptome transfer produces cellular phenotype conversion |
US8129187B2 (en) | 2005-12-13 | 2012-03-06 | Kyoto University | Somatic cell reprogramming by retroviral vectors encoding Oct3/4. Klf4, c-Myc and Sox2 |
EP2206724A1 (en) | 2005-12-13 | 2010-07-14 | Kyoto University | Nuclear reprogramming factor |
US9157066B2 (en) | 2005-12-13 | 2015-10-13 | The Trustees Of The University Of Pennsylvania | Transcriptome transfer produces cellular phenotype conversion |
JP5507086B2 (ja) | 2006-03-06 | 2014-05-28 | エージェンシー フォー サイエンス,テクノロジー アンド リサーチ | ヒト胚性幹細胞の方法及びpodxlの発現 |
JPWO2008102602A1 (ja) * | 2007-02-22 | 2010-05-27 | 国立大学法人 東京大学 | Blastocystcomplementationを利用した臓器再生法 |
AU2008231020B2 (en) | 2007-03-23 | 2013-09-05 | Wisconsin Alumni Research Foundation | Somatic cell reprogramming |
AU2016216711B2 (en) * | 2007-04-07 | 2018-01-25 | Whitehead Institute For Biomedical Research | Reprogramming of somatic cells |
CA2683056C (en) | 2007-04-07 | 2020-03-24 | Whitehead Institute For Biomedical Research | Reprogramming of somatic cells |
BRPI0810949A2 (pt) * | 2007-05-29 | 2015-10-27 | Christopher B Reid | "método de preparação de células multipotentes, auto-renovadoras, diferenciadoras ou resistentes a doenças, célula e vetor pra uso do método" |
US9213999B2 (en) | 2007-06-15 | 2015-12-15 | Kyoto University | Providing iPSCs to a customer |
JP2008307007A (ja) | 2007-06-15 | 2008-12-25 | Bayer Schering Pharma Ag | 出生後のヒト組織由来未分化幹細胞から誘導したヒト多能性幹細胞 |
US9080145B2 (en) | 2007-07-01 | 2015-07-14 | Lifescan Corporation | Single pluripotent stem cell culture |
EP2185693B1 (en) | 2007-07-31 | 2019-07-03 | Lifescan, Inc. | Differentiation of human embryonic stem cells |
WO2009032456A2 (en) * | 2007-08-01 | 2009-03-12 | Primegen Biotech Llc | Non-viral delivery of transcription factors that reprogram human somatic cells into a stem cell-like state |
CN101855338B (zh) * | 2007-08-31 | 2013-07-17 | 怀特黑德生物医学研究所 | 在程序重排体细胞中的wnt途径刺激 |
AU2008297024B2 (en) * | 2007-10-31 | 2014-08-28 | Kyoto University | Nuclear reprogramming method |
US9062290B2 (en) | 2007-11-27 | 2015-06-23 | Lifescan, Inc. | Differentiation of human embryonic stem cells |
WO2009073523A2 (en) * | 2007-11-29 | 2009-06-11 | Children's Hospital Of Orange County | De-differentiation of human cells |
JP5626619B2 (ja) * | 2008-12-08 | 2014-11-19 | 国立大学法人京都大学 | 効率的な核初期化方法 |
JP5558097B2 (ja) * | 2007-12-10 | 2014-07-23 | 国立大学法人京都大学 | 効率的な核初期化方法 |
US9683232B2 (en) * | 2007-12-10 | 2017-06-20 | Kyoto University | Efficient method for nuclear reprogramming |
WO2009076529A1 (en) | 2007-12-11 | 2009-06-18 | Research Development Foundation | Small molecules for neuronal differentiation of embryonic stem cells |
EP2072618A1 (en) * | 2007-12-14 | 2009-06-24 | Johannes Gutenberg-Universität Mainz | Use of RNA for reprogramming somatic cells |
KR101481164B1 (ko) * | 2008-01-30 | 2015-01-09 | 주식회사 미래셀바이오 | 체세포 유래 다능성 줄기세포의 제조 방법 |
WO2009096049A1 (ja) * | 2008-02-01 | 2009-08-06 | Kyoto University | 人工多能性幹細胞由来分化細胞 |
MX2010009251A (es) | 2008-02-21 | 2010-11-25 | Centocor Ortho Biotech Inc | Metodos, placas de superficie modificada y composiciones para la fijacion, el cultivo y el desprendimiento celular. |
JP5688788B2 (ja) * | 2008-02-22 | 2015-03-25 | 国立大学法人 東京大学 | 遺伝子改変による致死性表現型を持つ動物の繁殖用ファウンダー動物作製法 |
JP2009215191A (ja) | 2008-03-07 | 2009-09-24 | Keio Gijuku | 神経損傷治療剤及び神経損傷治療方法 |
EP2100954A1 (en) * | 2008-03-10 | 2009-09-16 | Assistance Publique - Hopitaux de Paris | Method for generating primate cardiac progenitor cells for clinical use from primate embryonic stem cells, and their applications |
ES2690554T3 (es) | 2008-03-17 | 2018-11-21 | The Scripps Research Institute | Enfoques químicos y genéticos combinados para la generación de células madre pluripotentes inducidas |
AU2015201026B2 (en) * | 2008-03-17 | 2017-03-16 | The Scripps Research Institute | Combined chemical and genetic approaches for generation of induced pluripotent stem cells |
WO2009114949A1 (en) * | 2008-03-20 | 2009-09-24 | UNIVERSITé LAVAL | Methods for deprogramming somatic cells and uses thereof |
US8765465B2 (en) | 2008-03-26 | 2014-07-01 | Kyoto University | Efficient production and use of highly cardiogenic progenitors and cardiomyocytes from embryonic and induced pluripotent stem cells |
JPWO2009119105A1 (ja) * | 2008-03-28 | 2011-07-21 | 国立大学法人 東京大学 | GPIbα+GPV+GPVI+血小板のインビトロ調製法 |
CA2718830C (en) * | 2008-03-31 | 2017-04-18 | Kyoto University | Method for proliferation of pluripotent stem cells |
JP5617631B2 (ja) * | 2008-04-01 | 2014-11-05 | 国立大学法人東京大学 | iPS細胞からの血小板の調製方法 |
WO2009146098A2 (en) * | 2008-04-02 | 2009-12-03 | President And Fellows Of Harvard College | Stem cells and uses thereof |
EP2276834A4 (en) * | 2008-04-07 | 2012-02-08 | Nupotential Inc | RE-PROGRAMMING A CELL BY INDUCING A PLURIPOTENTIC GENE ON THE USE OF A SMALL MOLECULE MODULATOR |
US20100021437A1 (en) * | 2008-04-07 | 2010-01-28 | The McLean Hospital Corporation Whitehead Institute for Biomedical Research | Neural stem cells derived from induced pluripotent stem cells |
US8623648B2 (en) * | 2008-04-24 | 2014-01-07 | Janssen Biotech, Inc. | Treatment of pluripotent cells |
WO2009131262A1 (en) * | 2008-04-25 | 2009-10-29 | Mirae Biotech Co., Ltd. | Method of manufacturing induced pluripotent stem cell originated from human somatic cell |
US20100279404A1 (en) | 2008-05-02 | 2010-11-04 | Shinya Yamanaka | Method of nuclear reprogramming |
US9102920B2 (en) * | 2008-05-06 | 2015-08-11 | Agency For Science, Technology And Research | Method of effecting de-differentiation of a cell |
EP2297298A4 (en) * | 2008-05-09 | 2011-10-05 | Vistagen Therapeutics Inc | PANCREATIC ENDOCRINE PROGENITOR CELLS FROM PLURIPOTENT STEM CELLS |
WO2009142717A2 (en) * | 2008-05-19 | 2009-11-26 | President And Fellows Of Harvard College | Methods and products for dedifferentiation of cells |
EP2128245A1 (en) * | 2008-05-27 | 2009-12-02 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Generation of induced pluripotent stem (iPS) cells |
JP2011160661A (ja) * | 2008-06-02 | 2011-08-25 | Kyowa Hakko Kirin Co Ltd | 血球細胞の初期化法 |
JP2011522540A (ja) | 2008-06-04 | 2011-08-04 | セルラー ダイナミクス インターナショナル, インコーポレイテッド | 非ウイルスアプローチを用いたiPS細胞の産生のための方法 |
AU2015202237B2 (en) * | 2008-06-13 | 2017-09-28 | Whitehead Institute For Biomedical Research | Programming and reprogramming of cells |
EP2300611B1 (en) | 2008-06-13 | 2017-08-09 | Whitehead Institute for Biomedical Research | Programming and reprogramming of cells |
US8669048B2 (en) * | 2008-06-24 | 2014-03-11 | Parkinson's Institute | Pluripotent cell lines and methods of use thereof |
WO2009157610A1 (en) * | 2008-06-26 | 2009-12-30 | Pusan National University Industry-University Cooperation Foundation | Selenium dedifferentiated cell, preparation method and usage thereof |
WO2009157201A1 (en) * | 2008-06-26 | 2009-12-30 | Osaka University | Method and kit for preparing ips cells |
KR101606943B1 (ko) | 2008-06-27 | 2016-03-28 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 유도된 다능성 줄기 세포의 효율적인 확립 방법 |
ES2697798T3 (es) | 2008-06-30 | 2019-01-28 | Janssen Biotech Inc | Diferenciación de células madre pluripotentes |
WO2010008054A1 (ja) | 2008-07-16 | 2010-01-21 | ディナベック株式会社 | 染色体非組み込み型ウイルスベクターを用いてリプログラムされた細胞を製造する方法 |
CN107012123A (zh) * | 2008-07-30 | 2017-08-04 | 国立大学法人京都大学 | 有效建立诱导的多能干细胞的方法 |
JP5553178B2 (ja) * | 2008-07-31 | 2014-07-16 | 国立大学法人岐阜大学 | 効率的な人工多能性幹細胞の樹立方法 |
EP2321406B1 (en) * | 2008-08-05 | 2014-12-10 | Keio University | Method for selecting secondary neurosphere derived from induced pluripotent stem cell |
WO2010017562A2 (en) | 2008-08-08 | 2010-02-11 | Mayo Foundation For Medical Education And Research | Induced pluripotent stem cells |
CN107988261A (zh) | 2008-08-12 | 2018-05-04 | 细胞动力国际有限公司 | 产生ips细胞的方法 |
AU2009282822A1 (en) * | 2008-08-21 | 2010-02-25 | Richter Gedeon Nyrt. | Methods for treating CNS disorders |
WO2010021390A1 (ja) * | 2008-08-22 | 2010-02-25 | 国立大学法人 東京大学 | iPS細胞とBLASTOCYST COMPLEMENTATIONを利用した臓器再生法 |
SG10201807935SA (en) * | 2008-09-04 | 2018-10-30 | Abt Holding Co | Use of stem cells to prevent neuronal dieback |
EP2333050A4 (en) | 2008-09-04 | 2013-07-03 | Riken | IPS CELLS FROM LYMPHOCYTES B AND APPLICATION THEREOF |
EP2336303B1 (en) * | 2008-09-08 | 2015-07-15 | Riken | NKT CELL-DERIVED iPS CELLS AND NKT CELLS DERIVED THEREFROM |
CA2736877A1 (en) * | 2008-09-12 | 2010-03-18 | Scarab Genomics, Llc | Clean genome bactofection |
CN101492676B (zh) * | 2008-09-16 | 2011-02-16 | 中国科学院广州生物医药与健康研究院 | 用脑膜细胞生成诱导的多能性干细胞的方法及其用途 |
SG160248A1 (en) * | 2008-09-18 | 2010-04-29 | Agency Science Tech & Res | Use of novel monoclonal antibodies targeting human embryonic stem cells to characterize and kill induced pluripotent stem cells |
WO2010033991A2 (en) | 2008-09-22 | 2010-03-25 | Children's Medical Center Corporation | Detection of human somatic cell reprogramming |
CN102203241B (zh) * | 2008-10-24 | 2017-05-03 | 可乐丽股份有限公司 | 细胞保存方法和细胞运输方法 |
EP2342333A4 (en) * | 2008-10-30 | 2013-05-08 | Univ Kyoto | METHOD FOR THE PRODUCTION OF INDUCED PLURIPOTENTAL STEM CELLS |
CN102333862B (zh) | 2008-10-31 | 2018-04-27 | 詹森生物科技公司 | 人胚胎干细胞向胰腺内分泌谱系的分化 |
CA2742268C (en) | 2008-10-31 | 2020-02-18 | Centocor Ortho Biotech Inc. | Differentiation of human embryonic stem cells to the pancreatic endocrine lineage |
EP2356223B1 (en) | 2008-11-05 | 2016-04-20 | Keio University | Method for producing neural stem cells |
CA2744227C (en) | 2008-11-20 | 2018-10-02 | Centocor Ortho Biotech Inc. | Methods and compositions for cell attachment and cultivation on planar substrates |
AU2009316580B2 (en) | 2008-11-20 | 2016-04-14 | Janssen Biotech, Inc. | Pluripotent stem cell culture on micro-carriers |
EP2192174B1 (en) * | 2008-11-21 | 2015-11-11 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Reprogramming cells toward a pluripotent state |
US20100150889A1 (en) | 2008-12-17 | 2010-06-17 | The Uab Research Foundation | Polycistronic Vector For Human Induced Pluripotent Stem Cell Production |
EP2373784B1 (en) * | 2008-12-17 | 2017-10-25 | The Scripps Research Institute | Generation and maintenance of stem cells |
WO2010071210A1 (ja) | 2008-12-18 | 2010-06-24 | 財団法人新産業創造研究機構 | 軟骨細胞様細胞、及びその製造方法 |
US10328103B2 (en) | 2009-01-03 | 2019-06-25 | Ray C. Wasielewski | Medical treatment composition comprising mammalian dental pulp stem cells |
US8470308B2 (en) * | 2009-01-03 | 2013-06-25 | Ray C. Wasielewski | Enhanced medical implant comprising disrupted tooth pulp and tooth particles |
KR20110106468A (ko) | 2009-02-03 | 2011-09-28 | 각고호우징 게이오기주크 | 인간 분화 세포-유래 다능성 줄기세포로부터 유래된 배아체 및/또는 신경 줄기세포의 배양방법 |
US20100209404A1 (en) * | 2009-02-10 | 2010-08-19 | University Of Dayton | Enhanced method for producing stem-like cells from somatic cells |
WO2010098419A1 (en) | 2009-02-27 | 2010-09-02 | Kyoto University | Novel nuclear reprogramming substance |
KR101764437B1 (ko) | 2009-03-20 | 2017-08-02 | 메소블라스트, 아이엔씨. | 재프로그램된 다분화능 세포의 생성 방법 |
JP5637354B2 (ja) * | 2009-03-30 | 2014-12-10 | 独立行政法人産業技術総合研究所 | 精製転写因子の調製法と細胞導入技術 |
US20120094304A1 (en) | 2009-04-17 | 2012-04-19 | Tohoku University | Method of preparing human lung tissue stem cells and method of inducing differentiation into human alveolar epithelial cells |
CN101613717B (zh) * | 2009-04-17 | 2012-01-11 | 中国科学院广州生物医药与健康研究院 | 用猪成纤维细胞生成诱导的多能性干细胞的方法 |
CN101580816B (zh) * | 2009-04-23 | 2012-02-29 | 中国科学院广州生物医药与健康研究院 | 诱导多能性干细胞快速高效产生的新型无血清培养基以及使用其的方法 |
JP2010268789A (ja) | 2009-04-24 | 2010-12-02 | Kumamoto Univ | 細胞医薬の製造方法 |
EP2253700A1 (en) | 2009-05-13 | 2010-11-24 | Helmholtz-Zentrum für Infektionsforschung GmbH | A method for producing test systems from donors suffering from adverse effects of medicaments and /or medical treatments, and uses of said systems |
ES2664590T3 (es) * | 2009-05-18 | 2018-04-20 | Curna, Inc. | Tratamiento de enfermedades relacionadas con factores de reprogramación por inhibición del tránscrito antisentido natural a un factor de reprogramación |
JP5777113B2 (ja) * | 2009-05-29 | 2015-09-09 | 学校法人慶應義塾 | 人工多能性幹細胞のクローンの選択方法 |
EP2438161B1 (en) | 2009-05-29 | 2017-08-30 | Univ Kyoto | PROCESS FOR THE PRODUCTION OF PLURIPOTENT STEM CELLS AND THEIR CULTURE PROCESS |
US9365866B2 (en) | 2009-06-03 | 2016-06-14 | National Institute Of Advanced Industrial Science And Technology | Vectors for generating pluripotent stem cells and methods of producing pluripotent stem cells using the same |
US20110002897A1 (en) * | 2009-06-11 | 2011-01-06 | Burnham Institute For Medical Research | Directed differentiation of stem cells |
US9550975B2 (en) * | 2009-07-15 | 2017-01-24 | Mari Dezawa | SSEA-3 pluripotent stem cell isolated from body tissue |
US9399758B2 (en) | 2009-07-15 | 2016-07-26 | Mari Dezawa | SSEA3(+) pluripotent stem cell that can be isolated from body tissue |
KR20170118969A (ko) | 2009-07-20 | 2017-10-25 | 얀센 바이오테크 인코포레이티드 | 인간 배아 줄기 세포의 분화 |
CN102471744B (zh) | 2009-07-21 | 2015-06-10 | 国立大学法人京都大学 | 图像处理装置、培养观察装置及图像处理方法 |
AU2010279913B2 (en) | 2009-08-07 | 2016-04-28 | Kyoto University | Method of efficiently establishing induced pluripotent stem cells |
JP5751548B2 (ja) | 2009-08-07 | 2015-07-22 | 国立大学法人京都大学 | イヌiPS細胞及びその製造方法 |
CN101993495B (zh) * | 2009-08-12 | 2013-07-24 | 上海近岸科技有限公司 | 一种蛋白质混合物及其制备方法 |
KR101755214B1 (ko) | 2009-08-12 | 2017-07-07 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 만능줄기세포의 신경전구세포로의 분화 유도 방법 |
US20120282318A1 (en) | 2009-08-19 | 2012-11-08 | Koyoto University | Sheet for corneal transplants |
DK2615460T3 (da) | 2009-08-22 | 2014-08-25 | Univ Leland Stanford Junior | Billeddannelse og evaluering af embryoer, oocyter, og stamceller |
US20110052549A1 (en) * | 2009-08-27 | 2011-03-03 | The Regents Of The University Of California | Cell culture device to differentiate stem cells in a specific orientation |
US8748179B2 (en) | 2009-08-31 | 2014-06-10 | Osaka University | Method for efficient production of induced pluripotent stem cells utilizing cells derived from oral mucosa |
US8741649B2 (en) | 2009-09-04 | 2014-06-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods for enhancing genome stability and telomere elongation in embryonic stem cells |
GB0915523D0 (en) | 2009-09-07 | 2009-10-07 | Genome Res Ltd | Cells and methods for obtaining them |
WO2011030915A1 (en) | 2009-09-08 | 2011-03-17 | Kyoto University | Method for producing mast cells from pluripotent stem cells |
WO2011032025A2 (en) * | 2009-09-10 | 2011-03-17 | The Salk Institute For Biological Studies | Adipose-derived induced pluripotent stem cells |
KR101834687B1 (ko) * | 2009-09-15 | 2018-03-05 | 고쿠리츠다이가쿠호우진 도쿄다이가쿠 | 분화 세포의 신규 제조법 |
AU2014240253B2 (en) * | 2009-09-15 | 2017-08-03 | The University Of Tokyo | Novel Method for Producing Differentiated Cells |
US8993329B2 (en) | 2009-09-24 | 2015-03-31 | Kyoto University | Method of efficiently establishing induced pluripotent stem cells |
SG10201406139RA (en) * | 2009-09-30 | 2014-11-27 | Agency Science Tech & Res | A nuclear receptor and mutant thereof and the use of the same in the reprogramming of cells |
BR112012008848A2 (pt) | 2009-10-16 | 2019-09-24 | Scripps Research Inst | composição, e, método in vitro ou ex vivo para induzir células de mamífero não-pluripotente em células tronco pluripotentes induzidas |
AU2010312291A1 (en) | 2009-10-29 | 2012-06-21 | Mcmaster University | Generating induced pluripotent stem cells and progenitor cells from fibroblasts |
GB0919773D0 (en) | 2009-11-12 | 2009-12-30 | Univ Nottingham | Induced pluripotent stem cell |
EP3633025B1 (en) | 2009-11-12 | 2022-09-14 | Technion Research & Development Foundation Ltd. | Culture media, cell cultures and methods of culturing pluripotent stem cells in an undifferentiated state |
US8716020B2 (en) | 2009-11-13 | 2014-05-06 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Reprogrammation of eukaryotic cells with engineered microvesicles |
US8889412B2 (en) | 2009-11-19 | 2014-11-18 | Agency For Science, Technology And Research | Methods of enhancing pluripotentcy |
CN102648274B (zh) | 2009-12-09 | 2013-07-31 | 国立大学法人京都大学 | 包含双呋脒腙的促进多能干细胞分化成心肌细胞的组合物 |
US20130115622A1 (en) | 2009-12-14 | 2013-05-09 | Kyoto University | Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis |
WO2011079017A2 (en) | 2009-12-23 | 2011-06-30 | Centocor Ortho Biotech Inc. | Differentiation of human embryonic stem cells |
JP2011135864A (ja) * | 2009-12-30 | 2011-07-14 | Korea Univ Research & Business Foundation | Oct4及びBmi1、またはその上位調節子を用いて体細胞から胚幹細胞類似細胞への逆分化を誘導する組成物及びこれを用いた胚幹細胞類似細胞の製造方法 |
CN102791857B (zh) | 2010-01-06 | 2017-03-15 | 国立大学法人鸟取大学 | 小鼠人工染色体载体 |
EP2526189B1 (en) | 2010-01-22 | 2016-10-12 | Kyoto University | Method for improving induced pluripotent stem cell generation efficiency |
JP5812492B2 (ja) | 2010-02-03 | 2015-11-11 | 国立研究開発法人国立がん研究センター | 誘導肝幹細胞及びその製造方法、並びに、該細胞の応用 |
JP5765746B2 (ja) | 2010-02-16 | 2015-08-19 | 国立大学法人京都大学 | 効率的な人工多能性幹細胞の樹立方法 |
CN102884188A (zh) | 2010-02-18 | 2013-01-16 | 国立大学法人大阪大学 | 诱导性多能干细胞的制备方法 |
SG10201501503VA (en) | 2010-03-01 | 2015-04-29 | Janssen Biotech Inc | Methods for purifying cells derived from pluripotent stem cells |
EP2542249A4 (en) | 2010-03-05 | 2013-08-07 | Tissue Genesis Inc | METHOD AND COMPOSITIONS FOR SUPPORTING TISSUE INTEGRATION AND INOCULATION OF TRANSPLANTED TISSUE AND TRANSPLANTED TREATED PENIS FABRIC WITH FAT FABRIC ACETIC COSTS |
US20130071919A1 (en) * | 2010-03-10 | 2013-03-21 | Kyoto University | Method of selecting induced pluripotent stem cell |
JP5909482B2 (ja) | 2010-03-31 | 2016-04-26 | ザ スクリプス リサーチ インスティテュート | 細胞の再プログラム |
CN103097521A (zh) | 2010-04-16 | 2013-05-08 | 学校法人庆应义塾 | 人工多能性干细胞的制造方法 |
CA2796616A1 (en) | 2010-04-21 | 2011-10-27 | Research Development Foundation | Methods and compositions related to dopaminergic neuronal cells |
US9249392B2 (en) | 2010-04-30 | 2016-02-02 | Cedars-Sinai Medical Center | Methods and compositions for maintaining genomic stability in cultured stem cells |
US9845457B2 (en) | 2010-04-30 | 2017-12-19 | Cedars-Sinai Medical Center | Maintenance of genomic stability in cultured stem cells |
CN102242146B (zh) * | 2010-05-10 | 2015-11-25 | 高丽大学校产学协力团 | 组合物和用其产生诱导全能干细胞的方法 |
RU2663339C1 (ru) | 2010-05-12 | 2018-08-03 | Янссен Байотек, Инк. | Дифференцирование эмбриональных стволовых клеток человека |
KR20130080444A (ko) | 2010-05-25 | 2013-07-12 | 도쿠리츠교세이호진 고쿠리츠간켄큐센터 | 생체 외에서 자기 복제 가능한 유도 전암 간세포 또는 유도 악성 간세포, 이들의 제조 방법, 및, 이들 세포의 응용 |
US9376664B2 (en) | 2010-06-14 | 2016-06-28 | The Scripps Research Institute | Reprogramming of cells to a new fate |
JP5936134B2 (ja) | 2010-06-15 | 2016-06-15 | 国立大学法人京都大学 | ヒト人工多能性幹細胞の選択方法 |
KR101861171B1 (ko) * | 2010-06-18 | 2018-05-31 | 후지필름 셀룰러 다이내믹스, 인코포레이티드 | 투석된 혈청이 있는 심근세포 배지 |
WO2012008301A1 (ja) | 2010-07-12 | 2012-01-19 | 国立大学法人鳥取大学 | siRNA導入による新規hiPSC作製法 |
US9121011B2 (en) | 2010-07-21 | 2015-09-01 | Kyoto University | Method for inducing differentiation of human pluripotent stem cell into intermediate mesoderm cell |
CA2807552A1 (en) | 2010-08-06 | 2012-02-09 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9938496B2 (en) | 2010-08-13 | 2018-04-10 | Kyoto University | Method of inducing differentiation from pluripotent stem cells to germ cells |
CA2838330C (en) | 2010-08-23 | 2021-01-26 | President And Fellows Of Harvard College | Optogenetic probes for measuring membrane potential |
US9499790B2 (en) | 2010-08-26 | 2016-11-22 | Kyoto University | Method for promoting differentiation of pluripotent stem cells into cardiac muscle cells |
EP2610249B1 (en) | 2010-08-26 | 2017-10-11 | Kyoto University | Pluripotent stem cell cardiomyocyte differentiation-promoting agent |
AU2011297075B2 (en) | 2010-08-30 | 2014-07-17 | Dnavec Corporation | Composition for inducing pluripotent stem cell, and use thereof |
EP3372672A1 (en) | 2010-08-31 | 2018-09-12 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells |
EP2611910B1 (en) | 2010-08-31 | 2018-01-17 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells |
BR112013004614A2 (pt) | 2010-08-31 | 2024-01-16 | Janssen Biotech Inc | Diferenciação de células-tronco pluripotentes |
WO2012029994A1 (en) | 2010-09-02 | 2012-03-08 | Kyoto University | Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis |
EP2616540A4 (en) | 2010-09-14 | 2014-02-19 | Univ Kyoto | METHOD OF EFFICIENTLY ESTABLISHING INDUCED PLURIPOTENT STEM CELLS |
WO2012037456A1 (en) | 2010-09-17 | 2012-03-22 | President And Fellows Of Harvard College | Functional genomics assay for characterizing pluripotent stem cell utility and safety |
ES2862955T3 (es) | 2010-10-01 | 2021-10-08 | Modernatx Inc | Acidos nucleicos manipulados y métodos de uso de los mismos |
WO2012051515A2 (en) * | 2010-10-14 | 2012-04-19 | University Of Central Florida Research Foundation, Inc. | Cardiac induced pluripotent stem cells and methods of use in repair and regeneration of myocardium |
EP2630232A4 (en) | 2010-10-22 | 2014-04-02 | Biotime Inc | METHOD FOR MODIFYING TRANSCRIPTIONAL REGULATORY NETWORKS IN STEM CELLS |
JP6044932B2 (ja) * | 2010-10-25 | 2016-12-14 | 公立大学法人横浜市立大学 | 幹細胞の安定的維持、複製を制御するためのペプチジルプロリルイソメラーゼPin1の利用 |
EP2636731B1 (en) | 2010-11-02 | 2016-07-13 | National University Corporation Kumamoto University | Method of producing intestinal cells |
JP5888753B2 (ja) * | 2010-11-04 | 2016-03-22 | 国立大学法人京都大学 | 効率的な人工多能性幹細胞の樹立方法 |
WO2012060109A1 (en) | 2010-11-05 | 2012-05-10 | Kyoto University | Method of examining polycystic kidney disease and method of screening for therapeutic agent of the disease |
JP5963309B2 (ja) * | 2010-11-09 | 2016-08-03 | 国立研究開発法人産業技術総合研究所 | 末梢血単球由来多能性幹細胞作製方法 |
EP2640829A4 (en) | 2010-11-17 | 2014-06-11 | Univ Kyoto | CARDIOMYOCYTE AND / OR CARDIOVORA CELL PROLIFERATING AGENTS AND METHOD FOR PROLIFERATING CARDIOMYOCYTES AND / OR CARDIOVORA CELLS |
JPWO2012074116A1 (ja) | 2010-12-02 | 2014-05-19 | 独立行政法人理化学研究所 | アロNKT細胞を用いた免疫療法およびそのためのT細胞抗原受容体(TCR)遺伝子のα鎖領域が均一なVα−Jαに再構成されている細胞および該細胞由来NKT細胞のバンキング |
WO2012074106A1 (ja) | 2010-12-03 | 2012-06-07 | 国立大学法人京都大学 | 多能性幹細胞からの好酸球の製造方法 |
EP2647699B1 (en) * | 2010-12-03 | 2020-04-01 | Kyoto University | Efficient method for establishing induced pluripotent stem cells |
JP5888852B2 (ja) * | 2010-12-08 | 2016-03-22 | 学校法人近畿大学 | 免疫不全動物を用いた細胞の製法 |
WO2012087965A2 (en) | 2010-12-22 | 2012-06-28 | Fate Therapauetics, Inc. | Cell culture platform for single cell sorting and enhanced reprogramming of ipscs |
WO2012100084A1 (en) | 2011-01-19 | 2012-07-26 | The Regents Of The University Of California | Somatic cells with innate potential for pluripotency |
WO2012098260A1 (en) | 2011-01-21 | 2012-07-26 | Axiogenesis Ag | A non-viral system for the generation of induced pluripotent stem (ips) cells |
WO2012112458A2 (en) * | 2011-02-14 | 2012-08-23 | The Regents Of The University Of California | Compositions and methods for increasing reprogramming efficiency |
JP5995247B2 (ja) | 2011-02-23 | 2016-09-21 | 国立大学法人京都大学 | 多能性幹細胞から樹状細胞を製造する方法 |
US9879307B2 (en) | 2011-02-23 | 2018-01-30 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of detecting aneuploidy in human embryos |
GB201103600D0 (en) | 2011-03-01 | 2011-04-13 | Isis Innovation | Dendritic cells |
ES2855577T3 (es) | 2011-03-30 | 2021-09-23 | Transine Therapeutics Ltd | Molécula de ácido nucleico funcional y uso de la misma |
JP6025067B2 (ja) | 2011-03-31 | 2016-11-16 | iHeart Japan株式会社 | 新規心筋細胞マーカー |
US8710200B2 (en) | 2011-03-31 | 2014-04-29 | Moderna Therapeutics, Inc. | Engineered nucleic acids encoding a modified erythropoietin and their expression |
WO2012133811A1 (ja) | 2011-03-31 | 2012-10-04 | 独立行政法人理化学研究所 | 未分化状態の制御剤およびその用途 |
ES2695550T3 (es) | 2011-04-08 | 2019-01-09 | Inst Nat Sante Rech Med | Método para rejuvenecer células |
JP5761826B2 (ja) | 2011-04-08 | 2015-08-12 | 国立大学法人大阪大学 | 改変ラミニンおよびその利用 |
WO2012141181A1 (ja) * | 2011-04-11 | 2012-10-18 | 国立大学法人京都大学 | 核初期化物質 |
CN103492555A (zh) | 2011-04-20 | 2014-01-01 | 国立大学法人大阪大学 | 角膜上皮分化取向性iPS细胞 |
EP2707479B1 (en) | 2011-05-13 | 2018-01-10 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Use of zscan4 and zscan4-dependent genes for direct reprogramming of somatic cells |
WO2012168434A1 (en) | 2011-06-08 | 2012-12-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Partial reprogramming of somatic cells to induced tissue stem (its) cells |
GB201110331D0 (en) | 2011-06-16 | 2011-08-03 | Isis Innovation | Method of cryopreserving pluripotent stem cells |
WO2013010045A1 (en) | 2011-07-12 | 2013-01-17 | Biotime Inc. | Novel methods and formulations for orthopedic cell therapy |
EP2734617B1 (en) | 2011-07-22 | 2017-04-12 | Centre National De La Recherche Scientifique | Use of cellular extracts for obtaining pluripotent stem cells |
US20130029416A1 (en) | 2011-07-22 | 2013-01-31 | Tayaramma Thatava | Differentiating induced pluripotent stem cells into glucose-responsive, insulin-secreting progeny |
CN103703130A (zh) | 2011-07-25 | 2014-04-02 | 国立大学法人京都大学 | 筛选诱导的多能干细胞的方法 |
WO2013031826A1 (ja) * | 2011-08-29 | 2013-03-07 | 国立大学法人京都大学 | 核初期化物質 |
US9145547B2 (en) | 2011-08-30 | 2015-09-29 | Riken | Nuclear reprogrammed cells generated by introduction of a histone H2aa or TH2A gene, a histone H2ba or TH2B gene, or a phosphorylation-mimic of histone chaperon Npm2 gene, an Oct family gene and a klf family gene into a mammalian somatic cell |
WO2013039087A1 (ja) | 2011-09-12 | 2013-03-21 | 国立大学法人 熊本大学 | 物質のスクリーニング方法 |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9480695B2 (en) | 2011-09-29 | 2016-11-01 | The University Of Tokyo | Methods for inducing orexin neurons and agent for treating narcolepsy or eating disorder |
JP6120223B2 (ja) * | 2011-09-29 | 2017-04-26 | 国立大学法人 東京大学 | オレキシンニューロンの誘導法 |
WO2013052523A1 (en) | 2011-10-03 | 2013-04-11 | modeRNA Therapeutics | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
CN103917641B (zh) | 2011-10-21 | 2018-04-27 | 爱科来株式会社 | 通过层流进行的维持多能性的单个分散细胞的培养法 |
GB2496375A (en) | 2011-10-28 | 2013-05-15 | Kymab Ltd | A non-human assay vertebrate comprising human antibody loci and human epitope knock-in, and uses thereof |
WO2013078433A1 (en) | 2011-11-23 | 2013-05-30 | University Of Hawaii | Auto-processing domains for polypeptide expression |
WO2013077423A1 (ja) | 2011-11-25 | 2013-05-30 | 国立大学法人京都大学 | 多能性幹細胞の培養方法 |
TW201335372A (zh) | 2011-11-30 | 2013-09-01 | Nat Cancer Ct | 誘導惡性幹細胞 |
GB201122047D0 (en) | 2011-12-21 | 2012-02-01 | Kymab Ltd | Transgenic animals |
WO2013086008A1 (en) | 2011-12-05 | 2013-06-13 | Factor Bioscience Inc. | Methods and products for transfecting cells |
US8497124B2 (en) | 2011-12-05 | 2013-07-30 | Factor Bioscience Inc. | Methods and products for reprogramming cells to a less differentiated state |
CN104114572A (zh) | 2011-12-16 | 2014-10-22 | 现代治疗公司 | 经修饰的核苷、核苷酸和核酸组合物 |
EP2794860B1 (en) | 2011-12-19 | 2017-05-03 | Kyoto University | Method for inducing differentiation of human pluripotent stem cells into intermediate mesoderm cells |
JP6441080B2 (ja) | 2011-12-22 | 2018-12-19 | ヤンセン バイオテツク,インコーポレーテツド | 単一ホルモンのインスリン陽性細胞へのヒト胚性幹細胞の分化 |
CN104039954B (zh) | 2011-12-27 | 2017-03-15 | 国立大学法人大阪大学 | 可抑制iPS细胞的肿瘤化的分化诱导方法 |
WO2013105098A1 (en) | 2012-01-15 | 2013-07-18 | Yeda Research And Development Co. Ltd. | Induction of dedifferentiation of mesenchymal stromal cells |
JP6274510B2 (ja) | 2012-01-27 | 2018-02-07 | 国立大学法人京都大学 | 多能性幹細胞の心筋分化誘導法 |
CA2866590A1 (en) | 2012-03-07 | 2013-09-12 | Janssen Biotech, Inc. | Defined media for expansion and maintenance of pluripotent stem cells |
WO2013137491A1 (ja) | 2012-03-15 | 2013-09-19 | 国立大学法人京都大学 | 人工多能性幹細胞から心筋および血管系混合細胞群を製造する方法 |
WO2013139429A1 (en) | 2012-03-21 | 2013-09-26 | Merck Patent Gmbh | Induced neural stem cells |
US20150064734A1 (en) | 2012-03-21 | 2015-03-05 | Kyoto University | Method for screening therapeutic and/or prophylactic agents for alzheimer's disease |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
EP2833920A2 (en) | 2012-04-02 | 2015-02-11 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
JP6112733B2 (ja) | 2012-04-06 | 2017-04-12 | 国立大学法人京都大学 | エリスロポエチン産生細胞の誘導方法 |
US10195229B2 (en) * | 2012-04-19 | 2019-02-05 | Elsa R. Flores | Generation of human induced pluripotent stem cells using nucleic acid sequences that inhibit Δ-NP63 and DGCR8 |
US10519425B2 (en) | 2012-05-23 | 2019-12-31 | Kyoto University | Highly efficient method for establishing induced pluripotent stem cell |
RS64622B1 (sr) | 2012-05-25 | 2023-10-31 | Univ California | Metode i sastavi za modifikaciju ciljane dnk upravljenu pomoću rnk i za modulaciju transkripcije upravljanu rnk |
US20130337487A1 (en) | 2012-05-31 | 2013-12-19 | Auxogyn, Inc. | In vitro embryo blastocyst prediction methods |
WO2013184527A1 (en) | 2012-06-05 | 2013-12-12 | Capricor, Inc. | Optimized methods for generation of cardiac stem cells from cardiac tissue and their use in cardiac therapy |
EP2859091B1 (en) | 2012-06-08 | 2018-08-29 | Janssen Biotech, Inc. | Differentiation of human embryonic stem cells into pancreatic endocrine cells |
CA2878163A1 (en) | 2012-07-11 | 2014-01-16 | Tissuetech, Inc. | Compositions containing hc-ha/ptx3 complexes and methods of use thereof |
US20150184129A1 (en) | 2012-07-17 | 2015-07-02 | Kyoto University | Novel cardiomyocyte marker |
KR102366081B1 (ko) | 2012-07-31 | 2022-02-23 | 에이지엑스 쎄라퓨틱스, 인크. | Hla g-변형된 세포 및 방법 |
CA2881394A1 (en) | 2012-08-13 | 2014-02-20 | Cedars-Sinai Medical Center | Exosomes and micro-ribonucleic acids for tissue regeneration |
WO2014027474A1 (ja) | 2012-08-17 | 2014-02-20 | 株式会社Clio | 心筋梗塞の修復再生を誘導する多能性幹細胞 |
US20150267174A1 (en) | 2012-10-09 | 2015-09-24 | Nakanobu Hayashi | Reprogramming peptide and use thereof |
JP2014082956A (ja) | 2012-10-19 | 2014-05-12 | Somar Corp | 細胞培養基材、およびそれを用いた細胞培養方法並びに多能性幹細胞の分化誘導方法 |
US10077429B2 (en) | 2012-10-23 | 2018-09-18 | Kyoto University | Method of efficiently establishing induced pluripotent stem cells |
JP6275646B2 (ja) | 2012-10-30 | 2018-02-07 | 第一三共株式会社 | Mait様細胞およびその作製方法 |
WO2014071219A1 (en) | 2012-11-01 | 2014-05-08 | Factor Bioscience Inc. | Methods and products for expressing proteins in cells |
PL2922554T3 (pl) | 2012-11-26 | 2022-06-20 | Modernatx, Inc. | Na zmodyfikowany na końcach |
GB201222693D0 (en) * | 2012-12-17 | 2013-01-30 | Babraham Inst | Novel method |
WO2014103137A1 (ja) | 2012-12-27 | 2014-07-03 | ソニー株式会社 | 細胞分析システム、細胞分析プログラム及び細胞分析方法 |
WO2014104364A1 (ja) | 2012-12-28 | 2014-07-03 | 国立大学法人京都大学 | 人工多能性幹細胞、心筋細胞又はその前駆細胞の製造方法 |
RU2684215C2 (ru) | 2012-12-31 | 2019-04-04 | Янссен Байотек, Инк. | Способ получения панкреатических эндокринных клеток (варианты) и способ увеличения выхода бета-клеток |
US10370644B2 (en) | 2012-12-31 | 2019-08-06 | Janssen Biotech, Inc. | Method for making human pluripotent suspension cultures and cells derived therefrom |
WO2014105543A1 (en) | 2012-12-31 | 2014-07-03 | Janssen Biotech, Inc. | Culturing of human embryonic stem cells at the air-liquid interface for differentiation into pancreatic endocrine cells |
MX2015008619A (es) | 2012-12-31 | 2016-01-12 | Janssen Biotech Inc | Suspension y agrupamiento de celulas humanas pluripotentes para la diferenciacion a celulas endocrinas pancreaticas. |
US20160017441A1 (en) | 2013-01-16 | 2016-01-21 | Universal Bio Research Co., Ltd. | Method for identifying cells |
WO2014121200A1 (en) | 2013-02-01 | 2014-08-07 | Auxogyn, Inc. | Abnormal syngamy phenotypes observed with time lapse imaging for early identification of embryos with lower developmental potential |
JP6426110B2 (ja) | 2013-02-01 | 2018-11-21 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | 人口多能性幹細胞(ipsc)由来の網膜色素上皮(rpe)細胞を生成するための方法 |
US10450546B2 (en) | 2013-02-06 | 2019-10-22 | University Of Rochester | Induced pluripotent cell-derived oligodendrocyte progenitor cells for the treatment of myelin disorders |
EP2955223B1 (en) | 2013-02-08 | 2019-12-18 | Kyoto University | Production methods for megakaryocytes and platelets |
JP6494903B2 (ja) | 2013-02-14 | 2019-04-03 | ソニー株式会社 | 分析システム、分析プログラム及び分析方法 |
EP2962698B1 (en) | 2013-03-01 | 2021-05-12 | Life Science Institute, Inc. | Pharmaceutical composition including migratory factor for guiding pluripotent stem cells to injury |
JP6292415B2 (ja) | 2013-03-06 | 2018-03-14 | 国立大学法人京都大学 | 多能性幹細胞の培養システム及び多能性幹細胞の継代方法 |
WO2014136519A1 (ja) | 2013-03-08 | 2014-09-12 | 国立大学法人京都大学 | Egf受容体阻害剤を含む多能性幹細胞の心筋分化促進剤 |
CN113564124A (zh) | 2013-03-14 | 2021-10-29 | 加利福尼亚大学董事会 | 内侧神经节***前体细胞的体外产生 |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
WO2014148646A1 (ja) | 2013-03-21 | 2014-09-25 | 国立大学法人京都大学 | 神経分化誘導用の多能性幹細胞 |
JP6473686B2 (ja) | 2013-03-25 | 2019-02-20 | 公益財団法人神戸医療産業都市推進機構 | 細胞の選別方法 |
GB201306589D0 (en) | 2013-04-11 | 2013-05-29 | Abeterno Ltd | Live cell imaging |
JP6461787B2 (ja) | 2013-04-12 | 2019-01-30 | 国立大学法人京都大学 | 肺胞上皮前駆細胞の誘導方法 |
JP6429280B2 (ja) | 2013-05-14 | 2018-11-28 | 国立大学法人京都大学 | 効率的な心筋細胞の誘導方法 |
US10159766B2 (en) | 2013-05-31 | 2018-12-25 | Iheart Japan Corporation | Layered cell sheet incorporating hydrogel |
US11085067B2 (en) | 2013-06-10 | 2021-08-10 | President And Fellows Of Harvard College | Early developmental genomic assay for characterizing pluripotent stem cell utility and safety |
WO2014200115A1 (ja) | 2013-06-11 | 2014-12-18 | 国立大学法人京都大学 | 腎前駆細胞の製造方法及び腎前駆細胞を含む医薬 |
JP6493881B2 (ja) | 2013-06-12 | 2019-04-03 | 国立大学法人京都大学 | 人工多能性幹細胞の選別方法および血球への分化誘導方法 |
JP6378183B2 (ja) | 2013-08-07 | 2018-08-22 | 国立大学法人京都大学 | 膵ホルモン産生細胞の製造法 |
US10030055B2 (en) | 2013-08-23 | 2018-07-24 | Riken | Polypeptide exhibiting fluorescent properties, and utilization of the same |
JP6617231B2 (ja) | 2013-08-28 | 2019-12-11 | 国立大学法人岐阜大学 | 人工多能性幹細胞の作製方法 |
WO2015030149A1 (ja) | 2013-08-29 | 2015-03-05 | 国立大学法人鳥取大学 | 細胞のアンチエイジングに関連する生体分子群 |
KR102320537B1 (ko) | 2013-09-05 | 2021-11-01 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 신규 도파민 생산 신경 전구 세포의 유도 방법 |
US9587230B2 (en) | 2013-09-05 | 2017-03-07 | Tempo Bioscience, Inc. | Human calcium binding domain biosensors |
WO2015037535A1 (ja) | 2013-09-12 | 2015-03-19 | 株式会社カネカ | 人工多能性幹細胞の分化誘導方法及び選別方法 |
JP6333830B2 (ja) | 2013-09-13 | 2018-05-30 | 国立大学法人京都大学 | 多能性幹細胞の心筋分化を促進する化合物 |
DK3050961T3 (da) | 2013-09-24 | 2023-08-14 | Id Pharma Co Ltd | Fremgangsmåde til forbedring af effektiviteten ved inducering af pluripotente stamceller |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
KR102219743B1 (ko) | 2013-11-01 | 2021-02-23 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 신규 연골 세포 유도 방법 |
WO2015066488A2 (en) | 2013-11-01 | 2015-05-07 | New England Biolabs, Inc. | Method for producing induced pluripotent stem cells |
US11767507B2 (en) | 2013-11-08 | 2023-09-26 | The Mclean Hospital Corporation | Methods for efficient generation of GABAergic interneurons from pluripotent stem cells |
US10163203B2 (en) | 2013-11-08 | 2018-12-25 | Sony Corporation | Cell analysis system, cell analysis program and cell analysis method |
US9932607B2 (en) | 2013-11-15 | 2018-04-03 | The Board Of Trustees Of The Leland Stanford Junior University | Site-specific integration of transgenes into human cells |
CN104630136B (zh) * | 2013-11-15 | 2019-10-01 | 中国科学院广州生物医药与健康研究院 | 一种制备诱导多能性干细胞的方法以及该方法中所使用的组合物及其应用 |
EP3760719A1 (en) | 2013-11-18 | 2021-01-06 | CRISPR Therapeutics AG | Crispr-cas system materials and methods |
JP6536871B2 (ja) | 2013-12-02 | 2019-07-03 | 国立大学法人京都大学 | Fgfr3病の予防および治療剤ならびにそのスクリーニング方法 |
KR102070967B1 (ko) * | 2013-12-10 | 2020-01-29 | 한국한의학연구원 | 사군자탕을 유효성분으로 포함하는, 세포의 유도만능줄기세포로의 리프로그래밍 촉진용 조성물 및 이를 이용한 유도만능줄기세포의 제조방법 |
BR112016012129A8 (pt) | 2013-12-11 | 2020-05-12 | Pfizer Ltd | métodos para produção, expansão e purificação de células epiteliais do pigmento da retina, composição farmacêutica e uso das células |
EP3835419A1 (en) | 2013-12-12 | 2021-06-16 | The Regents of The University of California | Methods and compositions for modifying a single stranded target nucleic acid |
JP6478116B2 (ja) | 2013-12-25 | 2019-03-06 | 東亞合成株式会社 | 多能性幹細胞から内胚葉系細胞への分化誘導方法 |
EP2896688A1 (en) | 2014-01-20 | 2015-07-22 | Centre National de la Recherche Scientifique (CNRS) | A method of producing beta pancreatic cells from progenitor cells through the use of hydrogen peroxide |
MX2016009771A (es) | 2014-01-31 | 2016-11-14 | Factor Bioscience Inc | Metodos y productos para la produccion y administracion de acido nucleico. |
EP3114214B1 (en) | 2014-03-04 | 2023-11-01 | Fate Therapeutics, Inc. | Improved reprogramming methods and cell culture platforms |
WO2015140257A1 (en) | 2014-03-19 | 2015-09-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for inducing human cholangiocyte differentiation |
US10538740B2 (en) | 2014-03-20 | 2020-01-21 | Kyoto University | Method for sorting cardiomyocytes |
EP3120297B1 (en) | 2014-03-20 | 2020-12-02 | Ares Trading S.A. | Quantitative measurement of human blastocyst and morula morphology developmental kinetics |
CN106164257B (zh) * | 2014-03-31 | 2021-03-09 | 味之素株式会社 | 干细胞用培养基 |
JP6588969B2 (ja) | 2014-05-16 | 2019-10-09 | ヤンセン バイオテツク,インコーポレーテツド | 膵内分泌細胞内のmafa発現を強化するための小分子の使用 |
EP3147353B1 (en) | 2014-05-21 | 2022-03-30 | Kyoto University | Method for producing pancreatic blast cells and pancreatic disease treatment agent containing pancreatic blast cells |
WO2015182765A1 (ja) | 2014-05-30 | 2015-12-03 | 国立大学法人京都大学 | 低分子化合物を用いた多能性幹細胞の心筋分化誘導法 |
US9518103B2 (en) | 2014-06-18 | 2016-12-13 | President And Fellows Of Harvard College | Optogenetic probes for measuring membrane potential |
US10138469B2 (en) | 2014-06-23 | 2018-11-27 | Toagosei Co., Ltd. | Synthetic peptide and use thereof |
JP7012432B2 (ja) | 2014-07-14 | 2022-01-28 | 中外製薬株式会社 | タンパク質のエピトープを同定するための方法 |
WO2016036754A1 (en) | 2014-09-02 | 2016-03-10 | The Regents Of The University Of California | Methods and compositions for rna-directed target dna modification |
JP6452107B2 (ja) | 2014-09-05 | 2019-01-16 | 国立大学法人 東京大学 | 糖尿病性皮膚潰瘍治療のための多能性幹細胞 |
CA2962444C (en) | 2014-10-03 | 2023-09-05 | Cedars-Sinai Medical Center | Cardiosphere-derived cells and exosomes secreted by such cells in the treatment of muscular dystrophy |
JP6598185B2 (ja) | 2014-11-07 | 2019-10-30 | 国立大学法人京都大学 | 軟骨過形成疾患の予防および治療剤ならびにそのスクリーニング方法 |
EP3223831B1 (en) | 2014-11-25 | 2020-06-24 | President and Fellows of Harvard College | Methods for generation of podocytes from pluripotent stem cells and cells produced by the same |
SI3233129T1 (sl) | 2014-12-17 | 2020-07-31 | Fundacion Para La Investigacion Medica Aplicada | Konstrukti nukleinske kisline in vektorji genske terapije za uporabo pri zdravljenju Wilsonove bolezni in drugih stanj |
ES2876412T3 (es) | 2014-12-17 | 2021-11-12 | Fundacion Para La Investig Medica Aplicada | Construcciones de ácido nucleico y vectores de terapia génica para su uso en el tratamiento de la enfermedad de Wilson |
US10711249B2 (en) | 2014-12-26 | 2020-07-14 | Kyoto University | Method for inducing hepatocytes |
US10077463B2 (en) | 2015-01-15 | 2018-09-18 | President And Fellows Of Harvard College | Optical selection of cells |
TWI696700B (zh) | 2015-01-16 | 2020-06-21 | 國立研究開發法人產業技術總合研究所 | 使用具有匿跡性之rna的基因表現系統及含有該rna的基因導入、表現載體 |
AU2016218977C1 (en) | 2015-02-13 | 2023-03-23 | Factor Bioscience Inc. | Nucleic acid products and methods of administration thereof |
JP2018510649A (ja) | 2015-02-17 | 2018-04-19 | ユニバーシティー ヘルス ネットワーク | 洞房結節様ペースメーカー心筋細胞および心室様心筋細胞を作製および使用するための方法 |
ES2703167T5 (es) | 2015-02-20 | 2022-09-30 | Inst Nat Sante Rech Med | Uso de una laminina para diferenciar células pluripotentes en células de linaje hepatocitario |
CA2978870A1 (en) | 2015-03-06 | 2016-09-15 | Kyoto University | Method for inducing differentiation of alveolar epithelial cells |
US10738280B2 (en) | 2015-03-18 | 2020-08-11 | Ono Pharmaceutical Co., Ltd. | Method for producing naïve pluripotent stem cells |
WO2016165788A1 (en) | 2015-04-14 | 2016-10-20 | Uab Ferentis | Collagen mimetic peptide |
EP3296390B1 (en) * | 2015-04-14 | 2023-01-04 | Kyoto University | Method for producing stem cell clones suitable for induction of differentiation into somatic cells |
JP2016202172A (ja) | 2015-04-16 | 2016-12-08 | 国立大学法人京都大学 | 疑似膵島の製造方法 |
US11359180B2 (en) | 2015-04-28 | 2022-06-14 | Toagosei Co., Ltd. | Method for producing myocardial cells using synthetic peptide |
US9724432B2 (en) | 2015-04-30 | 2017-08-08 | University Of Rochester | Non-human mammal model of human degenerative disorder, uses thereof, and method of treating human degenerative disorder |
FR3037338B1 (fr) | 2015-06-12 | 2020-02-28 | Philippe Nirde | Procede de greffe de cellule cardiaque sur la membrane choriallantoide d'œuf feconde |
WO2017002300A1 (en) | 2015-06-30 | 2017-01-05 | Sony Corporation | Information processing apparatus, information processing system, and information processing method |
JP6746945B2 (ja) | 2015-06-30 | 2020-08-26 | ソニー株式会社 | 情報処理装置、情報処理システム及び情報処理方法 |
EP3333256B1 (en) | 2015-07-10 | 2023-10-25 | Heartseed Inc. | Method for producing high-quality ips cells |
US10669529B2 (en) | 2015-07-17 | 2020-06-02 | Kyoto University | Method for inducing vascular endothelial cells |
JP7370529B2 (ja) | 2015-08-31 | 2023-10-30 | 剛士 田邊 | 多能性幹細胞製造システム、幹細胞の誘導方法、幹細胞の浮遊培養方法、幹細胞の浮遊培養器、人工多能性幹細胞の作製方法、及び動物細胞から特定の体細胞を作製する方法 |
ES2895676T3 (es) | 2015-09-01 | 2022-02-22 | Ncardia B V | Un método in vitro para diferenciar una población de células madre pluripotentes humanas en una población de células cardiomiocitas |
US20190169569A1 (en) | 2015-09-08 | 2019-06-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Method for reproducible differentiation of clinical-grade retinal pigment epithelium cells |
EP3347457B1 (en) | 2015-09-08 | 2021-10-27 | FUJIFILM Cellular Dynamics, Inc. | Macs-based purification of stem cell-derived retinal pigment epithelium |
TWI746459B (zh) | 2015-09-11 | 2021-11-21 | 日商安斯泰來製藥股份有限公司 | 製造腎前驅細胞之方法 |
JP2018532402A (ja) | 2015-09-24 | 2018-11-08 | クリスパー セラピューティクス アーゲー | Rnaプログラム可能エンドヌクレアーゼの新規のファミリーならびにゲノム編集および他の適用におけるそれらの使用 |
JP6691756B2 (ja) | 2015-09-29 | 2020-05-13 | 東亞合成株式会社 | 合成ペプチドを用いた神経幹細胞の生産方法 |
WO2017059241A1 (en) | 2015-10-02 | 2017-04-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Lentiviral protein delivery system for rna-guided genome editing |
EP3359169A4 (en) | 2015-10-05 | 2019-03-13 | Orig3N, Inc. | DIAGNOSIS AND TREATMENT OF MORBUS PARKINSON BASED ON THE IDENTIFICATION AND REDUCTION OF LIVER FUNCTIONAL DISORDERS |
CN117737124A (zh) | 2015-10-16 | 2024-03-22 | 菲特治疗公司 | 用于诱导和维护基态多能性的平台 |
CA3002157A1 (en) | 2015-10-20 | 2017-04-27 | FUJIFILM Cellular Dynamics, Inc. | Methods for directed differentiation of pluripotent stem cells to immune cells |
JP2016011317A (ja) * | 2015-10-21 | 2016-01-21 | 加治佐 功 | ゲノム編集用クリスパーキャス9による老化遺伝子切り取り若返り経口不老不死薬7 |
CA3005739A1 (en) | 2015-11-18 | 2017-05-26 | Orbis Health Solutions Llc | T7 alpha viral vector system |
US11253551B2 (en) | 2016-01-11 | 2022-02-22 | Cedars-Sinai Medical Center | Cardiosphere-derived cells and exosomes secreted by such cells in the treatment of heart failure with preserved ejection fraction |
GB201601503D0 (en) | 2016-01-27 | 2016-03-09 | Isis Innovation | Dendritic cells |
WO2017143071A1 (en) | 2016-02-18 | 2017-08-24 | The Regents Of The University Of California | Methods and compositions for gene editing in stem cells |
CA3017871A1 (en) | 2016-03-18 | 2017-09-21 | Kyoto University | Method for freezing aggregates of pluripotent stem cell-derived cardiomyocytes |
WO2017164746A1 (en) | 2016-03-25 | 2017-09-28 | Pluriomics B.V. | In vivo method for differentiating human pluripotent stem cells into atrial cardiomyocytes |
MA45479A (fr) | 2016-04-14 | 2019-02-20 | Janssen Biotech Inc | Différenciation de cellules souches pluripotentes en cellules de l'endoderme de l'intestin moyen |
PT3444334T (pt) | 2016-04-15 | 2021-09-08 | Univ Kyoto | Método para induzir células t cd8 positivas específicas de antigénio |
JP7011260B2 (ja) | 2016-04-22 | 2022-02-10 | 国立大学法人京都大学 | ドーパミン産生神経前駆細胞の製造方法 |
CA3024518C (en) | 2016-05-16 | 2022-02-15 | National University Corporation Nagoya University | Amelioration and treatment of perinatal brain damage with pluripotent stem cells |
US11351200B2 (en) | 2016-06-03 | 2022-06-07 | Cedars-Sinai Medical Center | CDC-derived exosomes for treatment of ventricular tachyarrythmias |
US20190330603A1 (en) | 2016-06-17 | 2019-10-31 | Genesis Technologies Limited | Crispr-cas system, materials and methods |
CA3029582A1 (en) | 2016-07-01 | 2018-01-04 | Research Development Foundation | Elimination of proliferating cells from stem cell-derived grafts |
EP3491134B1 (en) | 2016-08-01 | 2023-10-11 | University of Pittsburgh - of The Commonwealth System of Higher Education | Human induced pluripotent stem cells for high efficiency genetic engineering |
EP3494979A4 (en) | 2016-08-03 | 2020-03-04 | Life Science Institute, Inc. | REDUCTION AND TREATMENT OF ISCHEMIC REPERFUSION-INDUCED LUNG LESIONS USING PLURIPOTENTIC STEM CELLS |
CA3032917A1 (en) | 2016-08-03 | 2018-02-08 | National University Corporation Nagoya University | Amelioration and treatment of chronic lung disease using pluripotent stem cells |
US11259520B2 (en) | 2016-08-04 | 2022-03-01 | Fanuc Corporation | Stem cell manufacturing system, stem cell information management system, cell transport apparatus, and stem cell frozen storage apparatus |
US10354218B2 (en) | 2016-08-04 | 2019-07-16 | Fanuc Corporation | System and method for iPS cell bank using internet technology |
US10373109B2 (en) | 2016-08-04 | 2019-08-06 | Fanuc Corporation | System and method for iPS cell bank using media |
CA3033788A1 (en) | 2016-08-17 | 2018-02-22 | Factor Bioscience Inc. | Nucleic acid products and methods of administration thereof |
WO2018043714A1 (ja) | 2016-09-02 | 2018-03-08 | 塩野義製薬株式会社 | 多能性幹細胞からミクログリアを得る方法 |
WO2018057542A1 (en) | 2016-09-20 | 2018-03-29 | Cedars-Sinai Medical Center | Cardiosphere-derived cells and their extracellular vesicles to retard or reverse aging and age-related disorders |
WO2018067826A1 (en) | 2016-10-05 | 2018-04-12 | Cellular Dynamics International, Inc. | Generating mature lineages from induced pluripotent stem cells with mecp2 disruption |
US20190254264A1 (en) | 2016-10-31 | 2019-08-22 | National University Corporation Tottori University | Human antibody-producing non-human animal and method for preparing human antibodies using same |
US11458225B2 (en) | 2016-11-09 | 2022-10-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | 3D vascularized human ocular tissue for cell therapy and drug discovery |
KR102537361B1 (ko) | 2016-12-27 | 2023-05-26 | 스미또모 가가꾸 가부시키가이샤 | 인공 다능성 줄기 세포의 평가 방법 및 선발 방법, 그리고 인공 다능성 줄기 세포의 제조 방법 |
CN110199017A (zh) | 2017-01-20 | 2019-09-03 | 国立大学法人京都大学 | CD8α+β+细胞毒性T细胞的制备方法 |
JP7162537B2 (ja) | 2017-01-26 | 2022-10-28 | 国立大学法人大阪大学 | 幹細胞の中胚葉系細胞への分化誘導用培地および中胚葉系細胞の製造方法 |
EP4194549A1 (en) | 2017-01-27 | 2023-06-14 | Kaneka Corporation | Endodermal cell population, and method for producing cell population of any of three germ layers from pluripotent cell |
TW201835100A (zh) | 2017-02-06 | 2018-10-01 | 國立研究開發法人國立癌症研究中心 | 新穎t細胞受體 |
AU2018220843B2 (en) | 2017-02-14 | 2023-09-21 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods of engineering human induced pluripotent stem cells to produce liver tissue |
US10828330B2 (en) | 2017-02-22 | 2020-11-10 | IO Bioscience, Inc. | Nucleic acid constructs comprising gene editing multi-sites and uses thereof |
WO2018155607A1 (ja) | 2017-02-24 | 2018-08-30 | 剛士 田邊 | 細胞処理装置、浮遊培養器、及び幹細胞の誘導方法 |
EP3530727A4 (en) | 2017-02-27 | 2020-07-08 | Koji Tanabe | SOMATIC CELL PRODUCTION SYSTEM |
JP6530876B2 (ja) | 2017-02-27 | 2019-06-12 | 剛士 田邊 | 細胞処理システム及び細胞処理装置 |
US20190390169A1 (en) | 2017-03-03 | 2019-12-26 | Kyoto University | Pancreatic progenitor cell production method |
WO2018168829A1 (ja) | 2017-03-14 | 2018-09-20 | 国立大学法人京都大学 | 多能性幹細胞からヘルパーt細胞を製造する方法 |
JP7181534B2 (ja) | 2017-03-28 | 2022-12-01 | 味の素株式会社 | 未分化維持培地添加剤 |
EP4083063A3 (en) | 2017-04-18 | 2023-01-04 | FUJIFILM Cellular Dynamics, Inc. | Antigen-specific immune effector cells |
US11759482B2 (en) | 2017-04-19 | 2023-09-19 | Cedars-Sinai Medical Center | Methods and compositions for treating skeletal muscular dystrophy |
US20200197442A1 (en) * | 2017-04-26 | 2020-06-25 | Nsage Corp. | Pharmaceutical composition for prevention or treatment of alzheimer's disease, comprising stem cell secreting srage |
WO2018203499A1 (ja) | 2017-05-02 | 2018-11-08 | 剛士 田邊 | 医薬品組成物及び化粧品組成物 |
KR20230150412A (ko) | 2017-05-25 | 2023-10-30 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 중간 중배엽 세포로부터 신장 전구 세포로의 분화 유도 방법 및 다능성 줄기세포로부터 신장 전구 세포로의 분화 유도 방법 |
EP3406712A1 (en) | 2017-05-26 | 2018-11-28 | Fundación Centro Nacional De Investigaciones Oncológicas Carlos III | Method for expanding stemness and differentiation potential of pluripotent cells |
EP3640318A4 (en) | 2017-06-14 | 2021-03-17 | Takeda Pharmaceutical Company Limited | CELL SEALING DEVICE |
JP6758631B2 (ja) | 2017-06-19 | 2020-09-23 | 国立大学法人大阪大学 | 角膜内皮細胞マーカー及びその利用 |
KR102422175B1 (ko) | 2017-06-19 | 2022-07-18 | 고에키 자이단 호징 고베 이료 산교 도시 스이신 기코 | 만능 줄기 세포의 분화능의 예측 방법 및 이를 위한 시약 |
JP7255805B2 (ja) | 2017-06-20 | 2023-04-11 | 国立大学法人東海国立大学機構 | 多能性幹細胞による胎児発育不全に伴う脳障害の改善及び治療 |
US10660523B2 (en) | 2017-07-07 | 2020-05-26 | Hideo Ando | Light-source unit, measurement apparatus, near-infrared microscopic apparatus, optical detection method, imaging method, calculation method, functional bio-related substance, state management method, and manufacturing method |
EP3699267A4 (en) | 2017-10-17 | 2021-10-27 | Kyoto University | METHOD OF MANUFACTURING AN ARTIFICIAL NEUROMUSCULAR END PLATE FROM PLURIPOTENT STEM CELLS |
US20200237828A1 (en) | 2017-10-17 | 2020-07-30 | Hiroshima University | Pluripotent stem cells inducing osteochondral repair |
JP7202573B2 (ja) | 2017-11-02 | 2023-01-12 | 国立大学法人鳥取大学 | 哺乳類人工染色体ベクターを利用するタンパク質の高生産方法 |
EP3707256A1 (en) | 2017-11-09 | 2020-09-16 | CRISPR Therapeutics AG | Self-inactivating (sin) crispr/cas or crispr/cpf1 systems and uses thereof |
AU2018370029A1 (en) | 2017-11-15 | 2020-07-02 | Vertex Pharmaceuticals Incorporated | Islet cell manufacturing compositions and methods of use |
EA202091354A1 (ru) | 2017-11-30 | 2020-08-20 | Киото Юниверсити | Способ культивирования клеток |
WO2019118935A1 (en) | 2017-12-14 | 2019-06-20 | Casebia Therapeutics Limited Liability Partnership | Novel rna-programmable endonuclease systems and their use in genome editing and other applications |
US11660355B2 (en) | 2017-12-20 | 2023-05-30 | Cedars-Sinai Medical Center | Engineered extracellular vesicles for enhanced tissue delivery |
TWI821230B (zh) | 2017-12-22 | 2023-11-11 | 日商千紙鶴治療公司 | 細胞培養裝置、培養液吸引器及細胞培養方法 |
US20210095311A1 (en) | 2018-03-16 | 2021-04-01 | National University Corporation Tottori University | Mouse artificial chromosome vector and use thereof |
CN112424348A (zh) | 2018-03-19 | 2021-02-26 | 克里斯珀医疗股份公司 | 新颖的rna-可编程的内切核酸酶***及其用途 |
JPWO2019182157A1 (ja) | 2018-03-19 | 2021-03-18 | 国立大学法人京都大学 | ハイドロゲルカプセル |
WO2019180247A1 (en) | 2018-03-22 | 2019-09-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for reprogramming somatic cells |
JPWO2019189758A1 (ja) | 2018-03-30 | 2021-04-01 | 味の素株式会社 | ポリリジン類縁体を含む、細胞増殖促進用組成物 |
WO2019189545A1 (ja) | 2018-03-30 | 2019-10-03 | 国立大学法人京都大学 | 細胞の製造方法 |
WO2019189554A1 (ja) | 2018-03-30 | 2019-10-03 | 国立大学法人京都大学 | 心筋細胞成熟促進剤 |
SG11202009314XA (en) | 2018-03-30 | 2020-10-29 | Univ Kyoto | Heterocyclic compound |
US11268070B2 (en) | 2018-04-16 | 2022-03-08 | Cellular Engineering Technologies, Inc. | Methods for creating integration-free, virus-free, exogenous oncogene-free IPS cells and compositions for use in such methods |
JP2021521792A (ja) | 2018-04-20 | 2021-08-30 | フジフィルム セルラー ダイナミクス,インコーポレイテッド | 眼球細胞の分化方法及びその使用 |
SG11202009855WA (en) | 2018-04-23 | 2020-11-27 | Univ Kyoto | Growth inhibitor |
JP7311116B2 (ja) | 2018-04-27 | 2023-07-19 | 株式会社カネカ | 膵臓β細胞の製造方法 |
WO2019236766A1 (en) | 2018-06-06 | 2019-12-12 | Ideaya Biosciences, Inc. | Methods of culturing and/or expanding stem cells and/or lineage committed progenitor cells using lactam compounds |
CN112566640A (zh) | 2018-06-18 | 2021-03-26 | 罗切斯特大学 | 治疗精神***症和其他神经精神病症的方法 |
US20220062378A1 (en) | 2018-06-21 | 2022-03-03 | University Of Rochester | Methods of treating or inhibiting onset of huntington's disease |
BR112021000437A2 (pt) | 2018-07-13 | 2021-04-06 | Kyoto University | Métodos para produzir uma célula t gama delta e para prevenir ou tratar tumor, célula t gama delta, população de célula, medicamento, agente de extermínio para uma célula, e, uso da célula |
JP7285015B2 (ja) | 2018-07-19 | 2023-06-01 | 国立大学法人京都大学 | 多能性幹細胞由来の板状軟骨およびその製造方法 |
US20210332329A1 (en) | 2018-07-23 | 2021-10-28 | Kyoto University | Novel renal progenitor cell marker and method for concentrating renal progenitor cells using same |
US20210292708A1 (en) | 2018-08-03 | 2021-09-23 | Kyoto University | Cell production method |
SG11202100829SA (en) | 2018-08-10 | 2021-03-30 | Univ Kyoto | Method for producing cd3-positive cell |
WO2020033879A1 (en) | 2018-08-10 | 2020-02-13 | Semma Therapeutics, Inc. | Stem cell derived islet differentiation |
TW202035697A (zh) | 2018-08-10 | 2020-10-01 | 國立大學法人京都大學 | 使用陽離子性脂質對心肌細胞進行轉染的方法 |
CN112839667A (zh) | 2018-08-14 | 2021-05-25 | 国立研究开发法人国立国际医疗研究中心 | 褐色脂肪细胞上清、其制备法及使用 |
EP3842526A4 (en) | 2018-08-20 | 2022-05-25 | I Peace, Inc. | METHOD FOR CULTIVATING OR INDUCING CELLS |
WO2020040118A1 (ja) | 2018-08-20 | 2020-02-27 | アイ ピース, インコーポレイテッド | 細胞培養器 |
WO2020040166A1 (ja) | 2018-08-22 | 2020-02-27 | 国立大学法人京都大学 | 腸管神経前駆細胞の製造方法 |
KR20210053925A (ko) | 2018-08-31 | 2021-05-12 | 노일 이뮨 바이오테크 가부시키가이샤 | Car 발현 t 세포 및 car 발현 벡터 |
CN112867787A (zh) | 2018-09-19 | 2021-05-28 | 武田药品工业株式会社 | 胰岛素产生细胞 |
EP3800246A4 (en) | 2018-10-10 | 2022-04-20 | National University Corporation Tottori University | METHOD FOR THE PRODUCTION OF HUMAN INDUCED PLURIPOTENT STEM CELLS CONTAINING AN EXOGENOUS CHROMOSOME |
US20210163896A1 (en) | 2018-10-10 | 2021-06-03 | National University Corporation Tottori University | Method for producing animal cell containing dna of interest using micronucleate cell fusion method |
KR20210086638A (ko) | 2018-10-12 | 2021-07-08 | 비베트 테라퓨틱스 | 진행성 가족성 간내 담즙정체 3형 (pfic3)의 치료를 위한 코돈-최적화 전이유전자 |
US20220135938A1 (en) | 2018-10-15 | 2022-05-05 | Public University Corporation Yokohama City University | Nutrition composition |
US20220010283A1 (en) | 2018-10-31 | 2022-01-13 | Kyoto University | Method for producing pluripotent stem cell having released differentiation resistance to mesendoderm |
AU2019375450A1 (en) | 2018-11-07 | 2021-06-17 | Vivet Therapeutics | Codon-optimized ABCB11 transgene for the treatment of progressive familial intrahepatic cholestasis type 2 (PFIC2) |
EP4257155A3 (en) | 2018-11-16 | 2024-02-28 | Encoded Therapeutics, Inc. | Compositions and methods for treating wilson's disease |
WO2020106622A1 (en) | 2018-11-19 | 2020-05-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Biodegradable tissue replacement implant and its use |
EA202191463A1 (ru) | 2018-11-28 | 2021-10-13 | Борд Оф Риджентс, Дзе Юниверсити Оф Техас Систем | Мультиплексное редактирование генома иммунных клеток для повышения функциональности и устойчивости к подавляющей среде |
WO2020116606A1 (ja) | 2018-12-06 | 2020-06-11 | キリンホールディングス株式会社 | T細胞又はnk細胞の製造方法、t細胞又はnk細胞の培養用培地、t細胞又はnk細胞の培養方法、未分化t細胞の未分化状態を維持する方法及びt細胞又はnk細胞の増殖促進剤 |
JP2022511568A (ja) | 2018-12-11 | 2022-01-31 | ユニバーシティー オブ ロチェスター | 統合失調症及び他の神経精神障害の治療方法 |
US20220056413A1 (en) | 2018-12-21 | 2022-02-24 | Kyoto University | Lubricin-localized cartilage-like tissue, method for producing same and composition comprising same for treating articular cartilage damage |
US20220062341A1 (en) | 2018-12-26 | 2022-03-03 | Kirin Holdings Kabushiki Kaisha | Modified tcr and production method therefor |
KR20210109000A (ko) | 2018-12-27 | 2021-09-03 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | T-세포 수용체 개변체 |
EP3919124A4 (en) | 2019-02-01 | 2022-11-23 | Kyoto University | CELL DETECTION METHOD |
US20230057355A1 (en) | 2019-02-13 | 2023-02-23 | University Of Rochester | Gene networks that mediate remyelination of the human brain |
JPWO2020175592A1 (zh) | 2019-02-26 | 2020-09-03 | ||
JP2020141588A (ja) | 2019-03-05 | 2020-09-10 | ファナック株式会社 | 細胞製造システム |
AU2020231380A1 (en) | 2019-03-07 | 2021-09-23 | The Regents Of The University Of California | CRISPR-Cas effector polypeptides and methods of use thereof |
WO2020209959A1 (en) | 2019-03-08 | 2020-10-15 | Crispr Therapeutics Ag | Nucleobase-editing fusion protein systems, compositions, and uses thereof |
SG11202109741VA (en) | 2019-03-12 | 2021-10-28 | Crispr Therapeutics Ag | Novel high fidelity rna-programmable endonuclease systems and uses thereof |
JPWO2020203538A1 (zh) | 2019-03-29 | 2020-10-08 | ||
EP3950953A4 (en) | 2019-03-29 | 2023-04-19 | Public University Corporation Yokohama City University | SCREENING PROCEDURES AND TOXICITY ASSESSMENT PROCEDURES |
CA3136401A1 (en) | 2019-04-10 | 2020-10-15 | Orizuru Therapeutics, Inc. | Method for producing biological tissue-like structure |
EP3957722A4 (en) | 2019-04-17 | 2023-01-18 | Keio University | PRODUCTION PROCEDURE AND KIT OF INDUCED PLURIPOTENTS STEM CELLS |
EP3966327A1 (en) | 2019-05-08 | 2022-03-16 | Vertex Pharmaceuticals Incorporated | Crispr/cas all-in-two vector systems for treatment of dmd |
CN113811316A (zh) | 2019-05-15 | 2021-12-17 | 味之素株式会社 | 神经嵴细胞或角膜上皮细胞的纯化方法 |
EP3974519A4 (en) | 2019-05-20 | 2023-07-12 | Ajinomoto Co., Inc. | EXPANSION CULTURE METHOD FOR CARTILAGE OR BONE PRECURSOR CELLS |
JP7343881B2 (ja) | 2019-06-10 | 2023-09-13 | アイ ピース,インコーポレイテッド | 赤血球除去装置、単核球回収器、細胞培養装置、細胞培養システム、細胞培養方法、及び単核球の回収方法 |
EP3981446A4 (en) | 2019-06-10 | 2023-07-12 | I Peace, Inc. | DEVICE FOR REMOVING RED BLOOD CELLS, MONONUCLEAR CELL COLLECTOR, CELL CULTURE DEVICE, CELL CULTURE SYSTEM, CELL CULTURE PROCEDURE AND COLLECTION PROCEDURE FOR MONONUCLEAR CELLS |
EP3985104A4 (en) | 2019-06-11 | 2023-04-12 | Kyoto University | PROCEDURE FOR GENERATING A KIDNEY INTERSTITIAL CELL |
WO2020264072A1 (en) | 2019-06-25 | 2020-12-30 | Semma Therapeutics, Inc. | Enhanced differentiation of beta cells |
WO2020262351A1 (ja) | 2019-06-28 | 2020-12-30 | アイ ピース, インコーポレイテッド | 細胞塊分割器、細胞塊分割器の製造方法、及び細胞塊の分割方法 |
JP7041325B2 (ja) | 2019-06-28 | 2022-03-23 | アイ ピース,インコーポレイテッド | 細胞培養器及び細胞培養装置 |
US20220260580A1 (en) | 2019-07-19 | 2022-08-18 | Tokyo Electron Limited | Method for evaluating state of cell differentiation |
US10501404B1 (en) | 2019-07-30 | 2019-12-10 | Factor Bioscience Inc. | Cationic lipids and transfection methods |
WO2021030424A1 (en) | 2019-08-13 | 2021-02-18 | Semma Therapeutics, Inc. | Pancreatic differentiation |
JPWO2021033699A1 (zh) | 2019-08-20 | 2021-02-25 | ||
CN114341337A (zh) | 2019-08-29 | 2022-04-12 | 发那科株式会社 | 细胞制造装置 |
EP4023741A4 (en) | 2019-08-29 | 2023-11-08 | Fanuc Corporation | DEVICE FOR CELL PRODUCTION AND METHOD FOR CELL PRODUCTION |
CN114341340A (zh) | 2019-08-29 | 2022-04-12 | 发那科株式会社 | 细胞制造装置及其*** |
JPWO2021066076A1 (zh) | 2019-10-01 | 2021-04-08 | ||
CA3158631A1 (en) | 2019-10-21 | 2021-04-29 | Orizuru Therapeutics, Inc. | Growth inhibitor |
CA3156700A1 (en) | 2019-10-31 | 2021-05-06 | Life Science Institute, Inc. | Therapy for interstitial cystitis by pluripotent stem cells |
AR120348A1 (es) | 2019-11-01 | 2022-02-09 | Univ Kyoto | Método para producir células t |
JPWO2021090767A1 (zh) | 2019-11-06 | 2021-05-14 | ||
WO2021095811A1 (ja) | 2019-11-12 | 2021-05-20 | 学校法人順天堂 | 体細胞の直接分化転換方法 |
JPWO2021106832A1 (zh) | 2019-11-25 | 2021-06-03 | ||
CN115023233A (zh) | 2019-12-12 | 2022-09-06 | 国立大学法人千叶大学 | 包含巨核细胞和血小板的冷冻干燥制剂 |
FR3105260A1 (fr) | 2019-12-20 | 2021-06-25 | Centre National De La Recherche Scientifique (Cnrs) | Modèle organoïde cardiaque vascularisé apres incorporation de cardiomyocytes dérivés de cellules souches pluripotentes induites humaines |
MX2022010521A (es) | 2020-02-28 | 2022-09-19 | Takeda Pharmaceuticals Co | Metodo para producir linfocitos citoliticos naturales a partir de celulas madre pluripotentes. |
JP2023516484A (ja) | 2020-03-11 | 2023-04-19 | ビット バイオ リミテッド | 肝細胞作製方法 |
IL296353A (en) | 2020-03-13 | 2022-11-01 | Goliver Therapeutics | Hepatic stem-like cells and their uses in the treatment and or prevention of liver diseases |
EP4123010A4 (en) | 2020-03-18 | 2024-03-27 | Fanuc Corp | MICROSCOPE OBSERVATION SYSTEM |
EP4123016A1 (en) | 2020-03-19 | 2023-01-25 | Orizuru Therapeutics, Inc. | Method for purifying cardiomyocytes |
IL296317A (en) | 2020-03-19 | 2022-11-01 | Orizuru Therapeutics Inc | A method for purifying the cells of the heart |
EP4130239A1 (en) | 2020-03-24 | 2023-02-08 | Kaneka Corporation | Method for inducing differentiation into pancreatic alpha cells |
JPWO2021200901A1 (zh) | 2020-03-31 | 2021-10-07 | ||
CN115485388A (zh) | 2020-03-31 | 2022-12-16 | 天空制药株式会社 | 药物有效成分的筛选方法、制造方法和设计方法 |
JPWO2021241658A1 (zh) | 2020-05-26 | 2021-12-02 | ||
EP4159838A1 (en) | 2020-05-28 | 2023-04-05 | Orizuru Therapeutics, Inc. | Mass production method of uniform size cell aggregate |
WO2021243256A1 (en) | 2020-05-29 | 2021-12-02 | FUJIFILM Cellular Dynamics, Inc. | Retinal pigmented epithelium and photoreceptor dual cell aggregates and methods of use thereof |
MX2022015002A (es) | 2020-05-29 | 2023-03-03 | Fujifilm Cellular Dynamics Inc | Bicapa del epitelio pigmentario de la retina y fotorreceptores y uso de los mismos. |
WO2021250058A2 (en) | 2020-06-12 | 2021-12-16 | Bayer Aktiengesellschaft | CRISPR-Cas12a DIRECTED RANDOM MUTAGENESIS AGENTS AND METHODS |
US20230257705A1 (en) | 2020-06-17 | 2023-08-17 | Kyoto University | Chimeric antigen receptor-expressing immunocompetent cells |
WO2022014604A1 (ja) | 2020-07-13 | 2022-01-20 | 国立大学法人京都大学 | 骨格筋前駆細胞及びその精製方法、筋原性疾患を治療するための組成物、並びに骨格筋前駆細胞を含む細胞群の製造方法 |
JPWO2022019152A1 (zh) | 2020-07-20 | 2022-01-27 | ||
US20230265456A1 (en) | 2020-08-10 | 2023-08-24 | Fundacion Para La Investigacion Medica Aplicada | Gene therapy vector expressing cyp27a1 for the treatment of cerebrotendinous xanthomatosis |
EP4202041A1 (en) | 2020-08-18 | 2023-06-28 | Kyoto University | Method for maintaining and amplifying human primordial germ cells / human primordial germ cell-like cells |
EP4209593A1 (en) | 2020-09-04 | 2023-07-12 | Heartseed Inc. | Quality improving agent for ips cells, method of producing ips cells, ips cells, and composition for producing ips cells |
CA3200563A1 (en) | 2020-09-29 | 2022-04-07 | Genethon | Enhancing utrophin expression in cell by inducing mutations within utrophin regulatory elements and therapeutic use thereof |
IL302728A (en) | 2020-11-13 | 2023-07-01 | Catamaran Bio Inc | Genetically modified natural killer cells and methods of using them |
JPWO2022107877A1 (zh) | 2020-11-20 | 2022-05-27 | ||
US20220162288A1 (en) | 2020-11-25 | 2022-05-26 | Catamaran Bio, Inc. | Cellular therapeutics engineered with signal modulators and methods of use thereof |
JP2023553701A (ja) | 2020-12-16 | 2023-12-25 | ウニベルシタット ポンペウ ファブラ | 先天性筋ジストロフィーの処置のための治療用lama2ペイロード |
JP2022099262A (ja) | 2020-12-22 | 2022-07-04 | アイ ピース,インコーポレイテッド | 細胞の培養器及び細胞の培養方法 |
WO2022138101A1 (ja) | 2020-12-23 | 2022-06-30 | 三井化学株式会社 | 培養部材およびその用途 |
EP4267197A1 (en) | 2020-12-23 | 2023-11-01 | Vivet Therapeutics | Minimal bile acid inducible promoters for gene therapy |
WO2022138964A1 (ja) | 2020-12-25 | 2022-06-30 | 国立大学法人京都大学 | 体細胞からのナイーブ型ヒトiPS細胞製造方法 |
US20240093146A1 (en) * | 2021-01-26 | 2024-03-21 | Koji Tanabe | Method for producing oligodendrocytes |
CA3208794A1 (en) | 2021-02-09 | 2022-08-18 | Orizuru Therapeutics, Inc. | Maturation agent |
WO2022191171A1 (ja) | 2021-03-09 | 2022-09-15 | 国立大学法人 東京医科歯科大学 | 細胞クラスターの製造方法 |
WO2022196714A1 (ja) | 2021-03-17 | 2022-09-22 | アステラス製薬株式会社 | 塩基性繊維芽細胞増殖因子(bFGF)遺伝子が導入されたペリサイト |
EP4134086A1 (en) | 2021-08-12 | 2023-02-15 | Technische Universität Dresden | Human macrophages resistant to tumor-induced repolarization |
WO2022194930A1 (en) | 2021-03-19 | 2022-09-22 | Technische Universität Dresden | Human macrophages resistant to tumor-induced repolarization |
EP4060026A1 (en) | 2021-03-19 | 2022-09-21 | Technische Universität Dresden | Ex-vivo proliferation of human phagocytic cells |
WO2022207889A1 (en) | 2021-04-01 | 2022-10-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Liver organoid manufacturing methods, liver organoids obtained with the same, and uses thereof |
JPWO2022215718A1 (zh) | 2021-04-08 | 2022-10-13 | ||
CN117242171A (zh) | 2021-04-28 | 2023-12-15 | 国立大学法人东京医科齿科大学 | 用于产生细胞的方法 |
TW202305112A (zh) | 2021-04-30 | 2023-02-01 | 國立研究開發法人理化學研究所 | 視網膜色素上皮細胞之線狀凝集體,用於製造其之裝置及製造方法,以及含有該線狀凝集體之治療藥 |
WO2022236187A1 (en) | 2021-05-07 | 2022-11-10 | Children's Hospital Los Angeles | Methods for making stem cell-derived enteric neural crest cells and their use in enteric neuropathy treatment |
CN117881777A (zh) | 2021-05-26 | 2024-04-12 | 富士胶片细胞动力公司 | 防止多能干细胞中基因快速沉默的方法 |
WO2022251477A1 (en) | 2021-05-28 | 2022-12-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Biodegradable tissue scaffold with secondary matrix to host weakly adherent cells |
EP4347795A1 (en) | 2021-05-28 | 2024-04-10 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Methods to generate macular, central and peripheral retinal pigment epithelial cells |
WO2022258511A1 (en) | 2021-06-07 | 2022-12-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for generating highly functional hepatocytes by differentiating hepatoblasts |
CA3222761A1 (en) | 2021-06-10 | 2022-12-15 | Ajinomoto Co., Inc. | Method for producing mesenchymal stem cells |
EP4101928A1 (en) | 2021-06-11 | 2022-12-14 | Bayer AG | Type v rna programmable endonuclease systems |
BR112023023768A2 (pt) | 2021-06-11 | 2024-02-27 | Bayer Ag | Sistemas de endonucleases programáveis por rna tipo v |
AR126145A1 (es) | 2021-06-15 | 2023-09-13 | Takeda Pharmaceuticals Co | Método para producir linfocitos citolíticos naturales a partir de células madre pluripotentes |
CN117561328A (zh) | 2021-06-29 | 2024-02-13 | 国立大学法人佐贺大学 | iPS细胞来源的软骨细胞结构体的制造方法 |
WO2023286834A1 (ja) | 2021-07-15 | 2023-01-19 | アステラス製薬株式会社 | 血管内皮増殖因子(vegf)高発現ペリサイト様細胞 |
JPWO2023286832A1 (zh) | 2021-07-15 | 2023-01-19 | ||
JPWO2023003025A1 (zh) | 2021-07-21 | 2023-01-26 | ||
WO2023017848A1 (ja) | 2021-08-11 | 2023-02-16 | 国立大学法人京都大学 | 腎間質前駆細胞の製造方法並びにエリスロポエチン産生細胞、およびレニン産生細胞の製造方法 |
EP4144841A1 (en) | 2021-09-07 | 2023-03-08 | Bayer AG | Novel small rna programmable endonuclease systems with impoved pam specificity and uses thereof |
AU2022343749A1 (en) | 2021-09-13 | 2024-03-28 | FUJIFILM Cellular Dynamics, Inc. | Methods for the production of committed cardiac progenitor cells |
WO2023069979A1 (en) | 2021-10-20 | 2023-04-27 | University Of Rochester | Isolated glial progenitor cells for use in the competition treatment of age-related white matter loss |
US20230159890A1 (en) | 2021-10-20 | 2023-05-25 | University Of Rochester | Treatment with genetically modified cells, and genetically modified cells per se, with increased competitive advantage and/or decreased competitive disadvantage |
US20230292719A1 (en) | 2021-10-20 | 2023-09-21 | University Of Rochester | Humanized chimeras for the prospective assessment of cell addition and replacement therapies |
CA3234231A1 (en) | 2021-10-21 | 2023-04-27 | Vertex Pharmaceuticals Incorporated | Hypoimmune cells |
WO2023077140A2 (en) | 2021-11-01 | 2023-05-04 | Vertex Pharmaceuticals Incorporated | Stem cell derived pancreatic islet differentiation |
WO2023081633A1 (en) | 2021-11-02 | 2023-05-11 | University Of Rochester | Tcf7l2 mediated remyelination in the brain |
WO2023085433A1 (ja) | 2021-11-15 | 2023-05-19 | 国立大学法人鳥取大学 | ヒト細胞内でヒト人工染色体ベクターを作製する方法 |
WO2023090361A1 (ja) | 2021-11-16 | 2023-05-25 | 国立大学法人鳥取大学 | 改変d領域を含むヒト免疫グロブリン重鎖遺伝子座を有する哺乳動物人工染色体ベクター、及びそのベクターを保持する細胞又は非ヒト動物 |
WO2023118068A1 (en) | 2021-12-23 | 2023-06-29 | Bayer Aktiengesellschaft | Novel small type v rna programmable endonuclease systems |
WO2023150557A1 (en) | 2022-02-01 | 2023-08-10 | University Of Rochester | Methods of generating a population of neurons from human glial progenitor cells and genetic constructs for carrying out such methods |
WO2023167986A1 (en) | 2022-03-02 | 2023-09-07 | Lineage Cell Therapeutics, Inc. | Methods and compositions for treating hearing loss |
WO2023172514A1 (en) | 2022-03-07 | 2023-09-14 | Catamaran Bio, Inc. | Engineered immune cell therapeutics targeted to her2 and methods of use thereof |
WO2023211857A1 (en) | 2022-04-25 | 2023-11-02 | Lineage Cell Therapeutics, Inc. | Methods and compositions for treating vision loss |
WO2023215455A1 (en) | 2022-05-05 | 2023-11-09 | University Of Rochester | Dual macroglial-microglial approach towards therapeutic cell replacement in neurodegenerative and neuropsychiatric disease |
WO2023237587A1 (en) | 2022-06-10 | 2023-12-14 | Bayer Aktiengesellschaft | Novel small type v rna programmable endonuclease systems |
WO2023247532A1 (en) | 2022-06-21 | 2023-12-28 | Institut National de la Santé et de la Recherche Médicale | A method for producing a bioengineered mammal induced pluripotent stem cell-derived cardiac organoid |
US20240003871A1 (en) | 2022-06-29 | 2024-01-04 | FUJIFILM Cellular Dynamics, Inc. | Ipsc-derived astrocytes and methods of use thereof |
EP4338745A1 (en) | 2022-09-14 | 2024-03-20 | Technische Universität Dresden | Allogeneic human macrophages for cell therapy |
WO2024073776A1 (en) | 2022-09-30 | 2024-04-04 | FUJIFILM Cellular Dynamics, Inc. | Methods for the production of cardiac fibroblasts |
Family Cites Families (157)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US70292A (en) * | 1867-10-29 | Petess | ||
US4650761A (en) * | 1981-11-27 | 1987-03-17 | Eli Lilly And Company | Method for stabilizing and selecting recombinant DNA containing host cell |
US4650764A (en) | 1983-04-12 | 1987-03-17 | Wisconsin Alumni Research Foundation | Helper cell |
US4861719A (en) * | 1986-04-25 | 1989-08-29 | Fred Hutchinson Cancer Research Center | DNA constructs for retrovirus packaging cell lines |
US4937190A (en) * | 1987-10-15 | 1990-06-26 | Wisconsin Alumni Research Foundation | Translation enhancer |
US5192553A (en) * | 1987-11-12 | 1993-03-09 | Biocyte Corporation | Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use |
US6140111A (en) * | 1987-12-11 | 2000-10-31 | Whitehead Institute For Biomedical Research | Retroviral gene therapy vectors and therapeutic methods based thereon |
US7070994B2 (en) * | 1988-03-21 | 2006-07-04 | Oxford Biomedica (Uk) Ltd. | Packaging cells |
US5591624A (en) * | 1988-03-21 | 1997-01-07 | Chiron Viagene, Inc. | Retroviral packaging cell lines |
JP2886547B2 (ja) | 1988-07-26 | 1999-04-26 | 協和醗酵工業株式会社 | ノイラミニダーゼの製造法 |
JP3082204B2 (ja) * | 1988-09-01 | 2000-08-28 | ホワイトヘッド・インスティチュート・フォー・バイオメディカル・リサーチ | 両栄養性および環境栄養性宿主域を持つ組換え体レトロウイルス |
JP3051411B2 (ja) * | 1989-03-14 | 2000-06-12 | 持田製薬株式会社 | 新規dnaならびにそれを含有する発現プラスミド |
US5266491A (en) * | 1989-03-14 | 1993-11-30 | Mochida Pharmaceutical Co., Ltd. | DNA fragment and expression plasmid containing the DNA fragment |
JP2897295B2 (ja) * | 1989-12-14 | 1999-05-31 | 味の素株式会社 | レトロウィルス高生産用dna構築物及びレトロウィルス高生産用細胞株 |
US5652122A (en) * | 1989-12-21 | 1997-07-29 | Frankel; Alan | Nucleic acids encoding and methods of making tat-derived transport polypeptides |
US5817491A (en) * | 1990-09-21 | 1998-10-06 | The Regents Of The University Of California | VSV G pseusdotyped retroviral vectors |
US5288514A (en) * | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
US5834256A (en) * | 1993-06-11 | 1998-11-10 | Cell Genesys, Inc. | Method for production of high titer virus and high efficiency retroviral mediated transduction of mammalian cells |
FR2707091B1 (fr) | 1993-06-30 | 1997-04-04 | Cohen Haguenauer Odile | Vecteur rétroviral pour le transfert et l'expression de gènes dans des cellules eucaryotes. |
US5534423A (en) | 1993-10-08 | 1996-07-09 | Regents Of The University Of Michigan | Methods of increasing rates of infection by directing motion of vectors |
US5519134A (en) * | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
US6013517A (en) * | 1994-05-09 | 2000-01-11 | Chiron Corporation | Crossless retroviral vectors |
US5525735A (en) * | 1994-06-22 | 1996-06-11 | Affymax Technologies Nv | Methods for synthesizing diverse collections of pyrrolidine compounds |
US5549974A (en) * | 1994-06-23 | 1996-08-27 | Affymax Technologies Nv | Methods for the solid phase synthesis of thiazolidinones, metathiazanones, and derivatives thereof |
DK0787200T3 (da) * | 1994-10-28 | 2005-08-15 | Univ Pennsylvania | Forbedret adenovirus og fremgangsmåder til anvendelse heraf |
US5843780A (en) * | 1995-01-20 | 1998-12-01 | Wisconsin Alumni Research Foundation | Primate embryonic stem cells |
US5637456A (en) * | 1995-02-17 | 1997-06-10 | The University Of Texas, Board Of Regents | Rapid test for determining the amount of functionally inactive gene in a gene therapy vector preparation |
US5707618A (en) * | 1995-03-24 | 1998-01-13 | Genzyme Corporation | Adenovirus vectors for gene therapy |
US5830725A (en) * | 1995-04-28 | 1998-11-03 | The Board Of Trustees For The Leland Stanford Junior University | Rapid, stable high-titre production of recombing retrovirus |
US5744320A (en) * | 1995-06-07 | 1998-04-28 | Promega Corporation | Quenching reagents and assays for enzyme-mediated luminescence |
CN1208438A (zh) | 1995-07-28 | 1999-02-17 | 玛丽·柯里癌症治疗中心 | 转运蛋白及其应用 |
JP4053595B2 (ja) * | 1995-09-22 | 2008-02-27 | メディカル・リサーチ・カウンシル | 核酸の突然変異誘発におけるまたはそれに関する改良 |
US5910434A (en) * | 1995-12-15 | 1999-06-08 | Systemix, Inc. | Method for obtaining retroviral packaging cell lines producing high transducing efficiency retroviral supernatant |
FR2751345B1 (fr) * | 1996-07-16 | 1998-09-18 | Univ Paris Curie | Lignees d'encapsidation hautement productrices |
US6025192A (en) * | 1996-09-20 | 2000-02-15 | Cold Spring Harbor Laboratory | Modified retroviral vectors |
US6255071B1 (en) * | 1996-09-20 | 2001-07-03 | Cold Spring Harbor Laboratory | Mammalian viral vectors and their uses |
US6017735A (en) * | 1997-01-23 | 2000-01-25 | Marie Curie Cancer Care | Materials and methods for intracellular transport and their uses |
US6416959B1 (en) * | 1997-02-27 | 2002-07-09 | Kenneth Giuliano | System for cell-based screening |
AU9200398A (en) * | 1997-08-22 | 1999-03-16 | Yale University | A process to study changes in gene expression in granulocytic cells |
JPH11115328A (ja) * | 1997-10-16 | 1999-04-27 | Dainippon Printing Co Ltd | 熱転写受像シート及びその製造方法 |
US6835567B1 (en) * | 1998-04-14 | 2004-12-28 | Signal Pharmaceuticals, Inc. | PNS cell lines and methods of use therefor |
US20020174013A1 (en) | 1998-04-17 | 2002-11-21 | Viztec Inc., A Florida Corporation | Chip card advertising method and system |
EP1080218A1 (en) | 1998-05-27 | 2001-03-07 | University of Florida | Method of preparing recombinant adeno-associated virus compositions by using an iodixanol gradient |
KR20000006334A (ko) * | 1998-06-26 | 2000-01-25 | 이선경 | 바이러스코딩염기서열이전혀없는고효율레트로바이러스벡터 |
US6485959B1 (en) | 1998-10-07 | 2002-11-26 | Cedars Sinai Medical Center | Cell preconditioning and cryopresevation medium |
AU6339399A (en) | 1998-10-16 | 2000-05-08 | Novartis Ag | Promotion of self-renewal and improved gene transduction of hematopoietic stem cells by histone deacetylase inhibitors |
US6667176B1 (en) | 2000-01-11 | 2003-12-23 | Geron Corporation | cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells |
JP2002529070A (ja) * | 1998-11-09 | 2002-09-10 | モナシュ・ユニヴァーシティ | 胚性幹細胞 |
US6376246B1 (en) * | 1999-02-05 | 2002-04-23 | Maxygen, Inc. | Oligonucleotide mediated nucleic acid recombination |
US6153432A (en) * | 1999-01-29 | 2000-11-28 | Zen-Bio, Inc | Methods for the differentiation of human preadipocytes into adipocytes |
US6312949B1 (en) | 1999-03-26 | 2001-11-06 | The Salk Institute For Biological Studies | Regulation of tyrosine hydroxylase expression |
US6773920B1 (en) * | 1999-03-31 | 2004-08-10 | Invitrogen Corporation | Delivery of functional protein sequences by translocating polypeptides |
ATE391768T1 (de) * | 1999-06-01 | 2008-04-15 | Chugai Pharmaceutical Co Ltd | Verpackungszelle |
US7015037B1 (en) * | 1999-08-05 | 2006-03-21 | Regents Of The University Of Minnesota | Multiponent adult stem cells and methods for isolation |
WO2001015511A2 (en) * | 1999-09-01 | 2001-03-08 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Identification of peptides that facilitate uptake and cytoplasmic and/or nuclear transport of proteins, dna and viruses |
AU7611500A (en) | 1999-09-24 | 2001-04-24 | Abt Holding Company | Pluripotent embryonic-like stem cells, compositions, methods and uses thereof |
US20030161817A1 (en) * | 2001-03-28 | 2003-08-28 | Young Henry E. | Pluripotent embryonic-like stem cells, compositions, methods and uses thereof |
US6280718B1 (en) | 1999-11-08 | 2001-08-28 | Wisconsin Alumni Reasearch Foundation | Hematopoietic differentiation of human pluripotent embryonic stem cells |
US7544509B2 (en) * | 2000-01-24 | 2009-06-09 | Mcgill University | Method for preparing stem cell preparations |
US6395546B1 (en) | 2000-02-01 | 2002-05-28 | Neurogeneration, Inc. | Generation of dopaminergic neurons from human nervous system stem cells |
US7439064B2 (en) * | 2000-03-09 | 2008-10-21 | Wicell Research Institute, Inc. | Cultivation of human embryonic stem cells in the absence of feeder cells or without conditioned medium |
US6458589B1 (en) | 2000-04-27 | 2002-10-01 | Geron Corporation | Hepatocyte lineage cells derived from pluripotent stem cells |
GB2379447B (en) | 2000-05-17 | 2004-12-29 | Geron Corp | Neural progenitor cell populations |
US20020090722A1 (en) * | 2000-06-15 | 2002-07-11 | Tanja Dominko | Pluripotent mammalian cells |
DE10031179A1 (de) | 2000-06-27 | 2002-01-31 | Amaxa Gmbh | Verfahren zur Einbringung von Nukleinsäuren und anderen biologisch aktiven Molekülen in den Kern höherer eukaryontischer Zellen mit Hilfe elektrischen Stroms |
EP1305333A4 (en) * | 2000-07-31 | 2006-04-12 | Active Motif | ADMINISTRATION OF MOLECULES IN CELLS BY PEPTIDE MEDIATION |
JP2002065261A (ja) | 2000-08-30 | 2002-03-05 | Mitsubishi Kasei Institute Of Life Sciences | 生殖細胞の取得方法 |
DE50109634D1 (de) * | 2000-08-31 | 2006-06-01 | Edwin Lundgren | Steuervorrichtung für einen lenkdrachen an einem boot |
IL156132A0 (en) | 2000-11-27 | 2003-12-23 | Yissum Res Dev Co | Transfection of human embryonic stem cells |
US20080268054A1 (en) | 2000-12-04 | 2008-10-30 | Eugene Bell | Dermal derived human stem cells and compositions and methods thereof |
EP1373474A2 (en) | 2001-01-02 | 2004-01-02 | Stemron, Inc. | A method for producing a population of homozygous stem cells having a pre-selected immunophenotype and/or genotype |
EP1356024A2 (en) * | 2001-01-31 | 2003-10-29 | Interface Biotech A/S | An improved in vitro method of culturing mammalian cells for autologous cell implantation/transplantation methods |
JP2003009854A (ja) | 2001-04-09 | 2003-01-14 | Kyowa Hakko Kogyo Co Ltd | エンブリオイドボディ形成方法及びその用途 |
ATE278796T1 (de) | 2001-04-23 | 2004-10-15 | Amaxa Gmbh | Pufferlössung für die elektroporation und verfahren umfassend die verwendung derselben |
DE10119901A1 (de) | 2001-04-23 | 2002-10-24 | Amaxa Gmbh | Schaltungsanordnung zur Einbringung von Nukleinsäuren und anderen biologisch aktiven Molekülen in den Kern höherer eukaryontischer Zellen mit Hilfe elektrischen Stroms |
US7250255B2 (en) * | 2001-05-31 | 2007-07-31 | Shinya Yamanaka | Genes with ES cell-specific expression |
US20030044976A1 (en) * | 2001-08-27 | 2003-03-06 | Advanced Cell Technology | De-differentiation and re-differentiation of somatic cells and production of cells for cell therapies |
US20050079606A1 (en) * | 2001-09-20 | 2005-04-14 | Kyowa Hakko Kogyo Co., Ltd. | Pluripotent stem cells originating in skeletal muscle intestinal tissue |
JP2004248505A (ja) | 2001-09-21 | 2004-09-09 | Norio Nakatsuji | 移植抗原の一部または全てを欠除したes細胞由来の未分化な体細胞融合細胞およびその製造 |
JPWO2003027277A1 (ja) | 2001-09-21 | 2005-01-06 | 独立行政法人 科学技術振興機構 | 再プログラム化因子のスクリーニング方法、該方法によりスクリーニングされた再プログラム化因子および該再プログラム化因子を利用する方法、並びに、未分化融合細胞を分化させる方法および細胞、組織、臓器の製造方法 |
US7588937B2 (en) * | 2001-10-03 | 2009-09-15 | Wisconsin Alumni Research Foundation | Method of in vitro differentiation of neural stem cells, motor neurons and dopamine neurons from primate embryonic stem cells |
DE10162080A1 (de) * | 2001-12-10 | 2003-06-26 | Albrecht Mueller | Verfahren zur Herstellung von Stammzellen mit erhöhtem Entwicklungspotential |
JP2005512592A (ja) * | 2001-12-21 | 2005-05-12 | マウント・シナイ・ホスピタル | 細胞性組成物ならびに細胞性組成物の作製法および細胞性組成物の使用法 |
AU2003238620B2 (en) * | 2002-01-31 | 2008-11-06 | Asahi Techno Glass Corporation | Liquid for frozen storage of primate embryo stem cells and frozen storage method |
KR101176146B1 (ko) * | 2002-02-13 | 2012-08-22 | 안트로제네시스 코포레이션 | 산후 포유류 태반으로부터 유래한 배아-유사 줄기 세포와그 세포를 사용한 용도 및 치료방법 |
ES2198216B1 (es) * | 2002-07-02 | 2005-04-16 | Juan Carlos Instituto Cientifico Y Tecnologico De Navarra, S.A.(67%). | Medio de cultivo de celulas madre-progenitoras autologas humanas y sus aplicaciones. |
US7422736B2 (en) | 2002-07-26 | 2008-09-09 | Food Industry Research And Development Institute | Somatic pluripotent cells |
US20040048297A1 (en) * | 2002-07-30 | 2004-03-11 | Gene Logic, Inc. | Nucleic acid detection assay control genes |
JP3736517B2 (ja) * | 2002-11-13 | 2006-01-18 | 学校法人近畿大学 | 体細胞核初期化因子 |
AU2003901099A0 (en) | 2003-03-11 | 2003-03-27 | Es Cell International Pte Ltd. | Methods of inducing differentiation of stem cells |
KR100975254B1 (ko) * | 2003-03-25 | 2010-08-11 | 도쿠리쓰교세이호징 가가쿠 기주쓰 신코 기코 | 줄기 세포의 분화 유도 및 분화능의 제어 |
CN1536076A (zh) * | 2003-04-09 | 2004-10-13 | 中国人民解放军军事医学科学院野战输 | 成年人骨髓间充质干细胞体外扩增和定向诱导分化为心肌样细胞的方法 |
US9567591B2 (en) | 2003-05-15 | 2017-02-14 | Mello Biotechnology, Inc. | Generation of human embryonic stem-like cells using intronic RNA |
JPWO2004101775A1 (ja) * | 2003-05-16 | 2006-07-13 | 協和醗酵工業株式会社 | 新規な成体組織由来の幹細胞およびその用途 |
WO2005010524A1 (en) * | 2003-06-04 | 2005-02-03 | Curis, Inc. | Stem cell-based methods for identifying and characterizing agents |
FR2859219B1 (fr) * | 2003-09-02 | 2005-10-14 | Alain Privat | Procede de production de neurones a partir de cellules d'une lignee cellulaire |
JP2005095027A (ja) | 2003-09-22 | 2005-04-14 | Reprocell Inc | 細胞の未分化状態マーカープロモーターおよびその利用 |
JPWO2005035741A1 (ja) | 2003-10-09 | 2006-12-21 | 協和醗酵工業株式会社 | ゲノムが改変された細胞 |
WO2005047524A2 (en) | 2003-11-10 | 2005-05-26 | The Scripps Research Institute | Compositions and methods for inducing cell dedifferentiation |
US7682828B2 (en) * | 2003-11-26 | 2010-03-23 | Whitehead Institute For Biomedical Research | Methods for reprogramming somatic cells |
WO2005053601A2 (en) | 2003-12-01 | 2005-06-16 | Technion Research & Development Foundation Ltd. | Methods of generating stem cells and embryonic bodies carrying disease-causing mutations and methods of using same for studying genetic disorders |
WO2005065354A2 (en) * | 2003-12-31 | 2005-07-21 | The Burnham Institute | Defined media for pluripotent stem cell culture |
WO2005080598A1 (ja) * | 2004-02-19 | 2005-09-01 | Dainippon Sumitomo Pharma Co., Ltd. | 体細胞核初期化物質のスクリーニング方法 |
KR101178786B1 (ko) * | 2004-03-23 | 2012-09-07 | 다이이찌 산쿄 가부시키가이샤 | 다능성 줄기세포의 증식 방법 |
EP1741776A4 (en) * | 2004-03-30 | 2007-05-30 | Univ Kyoto | METHOD FOR PRODUCING A MULTIPOTENTIAL STEM CELL FROM A TESTOID CELL |
CA2568772A1 (en) * | 2004-06-01 | 2005-12-15 | San Diego State University Foundation | Expression system based on recombinant vesicular stomatitis virus synthesizing t7 rna polymerase |
US20070202592A1 (en) * | 2004-07-08 | 2007-08-30 | Yasuo Kitagawa | Pluripotent Cells Distributed Ubiquitously In Animal Tissue, Which Proliferate Selectively In Lower-Serum Culture |
WO2006084229A2 (en) | 2004-07-15 | 2006-08-10 | Primegen Biotech, Llc | Use of nuclear material to therapeutically reprogram differentiated cells |
US20060088599A1 (en) * | 2004-08-02 | 2006-04-27 | Prasad Paras N | Amino functionalized ORMOSIL nanoparticles as delivery vehicles |
JPWO2006035741A1 (ja) | 2004-09-29 | 2008-05-15 | 伸弥 山中 | Es細胞特異的発現遺伝子及びその利用 |
US20060095319A1 (en) * | 2004-10-29 | 2006-05-04 | Cardwell Carlzo B | Marketing and compensation method |
WO2006088867A2 (en) | 2005-02-15 | 2006-08-24 | Medistem Laboratories, Incorporated | Method for expansion of stem cells |
JPWO2006093172A1 (ja) * | 2005-02-28 | 2008-08-07 | 財団法人先端医療振興財団 | 成体幹細胞の体外増幅方法 |
US20070033061A1 (en) * | 2005-04-05 | 2007-02-08 | Achaogen, Inc. | Business methods for commercializing antimicrobial and cytotoxic compounds |
WO2007026255A2 (en) | 2005-06-22 | 2007-03-08 | Universitetet I Oslo | Dedifferentiated cells and methods of making and using dedifferentiated cells |
CN101313065A (zh) * | 2005-08-01 | 2008-11-26 | 纽珀滕索有限公司 | 具有恢复的潜能的重编程序细胞的生产 |
JP2009515515A (ja) | 2005-11-11 | 2009-04-16 | ザ・ユニバーシティ・コート・オブ・ザ・ユニバーシティ・オブ・エディンバラ | 細胞の再プログラム化および遺伝子改変 |
EP2206724A1 (en) | 2005-12-13 | 2010-07-14 | Kyoto University | Nuclear reprogramming factor |
US20090227032A1 (en) * | 2005-12-13 | 2009-09-10 | Kyoto University | Nuclear reprogramming factor and induced pluripotent stem cells |
US8278104B2 (en) * | 2005-12-13 | 2012-10-02 | Kyoto University | Induced pluripotent stem cells produced with Oct3/4, Klf4 and Sox2 |
US8129187B2 (en) * | 2005-12-13 | 2012-03-06 | Kyoto University | Somatic cell reprogramming by retroviral vectors encoding Oct3/4. Klf4, c-Myc and Sox2 |
CN101389761A (zh) | 2006-02-27 | 2009-03-18 | 银怎株式会社 | 使用bmi-1使星形胶质细胞去分化成为神经干细胞 |
US20090252711A1 (en) | 2006-05-11 | 2009-10-08 | Andrew Craig Boquest | Stem Cells And Methods Of Making And Using Stem Cells |
WO2008030610A2 (en) | 2006-09-08 | 2008-03-13 | Michigan State University | Human transcriptome corresponding to human oocytes and use of said genes or the corresponding polypeptides to trans-differentiate somatic cells |
JP2008099662A (ja) | 2006-09-22 | 2008-05-01 | Institute Of Physical & Chemical Research | 幹細胞の培養方法 |
US20080132803A1 (en) * | 2006-11-30 | 2008-06-05 | Hyman Friedlander | Method and system for doing business by mining the placental-chord complex |
JP5419279B2 (ja) | 2007-01-17 | 2014-02-19 | ウィスコンシン アラムニ リサーチ ファンデーション | 改良された幹細胞の培養 |
WO2008105566A1 (en) | 2007-02-27 | 2008-09-04 | Korea Stem Cell Bank | System for providing stem cell services using internet and method thereof |
WO2008105630A1 (en) | 2007-02-27 | 2008-09-04 | Procell Therapeutics Inc. | Combined use of cell permeable nanog and oct4 for increasing self-renewal and suppressing differentiation of stem cells |
AU2008231020B2 (en) | 2007-03-23 | 2013-09-05 | Wisconsin Alumni Research Foundation | Somatic cell reprogramming |
CA2683056C (en) | 2007-04-07 | 2020-03-24 | Whitehead Institute For Biomedical Research | Reprogramming of somatic cells |
BRPI0810949A2 (pt) | 2007-05-29 | 2015-10-27 | Christopher B Reid | "método de preparação de células multipotentes, auto-renovadoras, diferenciadoras ou resistentes a doenças, célula e vetor pra uso do método" |
US20100184051A1 (en) * | 2007-05-30 | 2010-07-22 | The General Hospital Corporation | Methods of generating pluripotent cells from somatic cells |
US9213999B2 (en) | 2007-06-15 | 2015-12-15 | Kyoto University | Providing iPSCs to a customer |
JP2008307007A (ja) * | 2007-06-15 | 2008-12-25 | Bayer Schering Pharma Ag | 出生後のヒト組織由来未分化幹細胞から誘導したヒト多能性幹細胞 |
WO2009032456A2 (en) | 2007-08-01 | 2009-03-12 | Primegen Biotech Llc | Non-viral delivery of transcription factors that reprogram human somatic cells into a stem cell-like state |
EP2190976A4 (en) | 2007-08-10 | 2010-10-20 | Univ Dayton | METHOD FOR PRODUCING PLURIPOTENTAL STEM CELL LENGTH CELLS |
CN101855338B (zh) | 2007-08-31 | 2013-07-17 | 怀特黑德生物医学研究所 | 在程序重排体细胞中的wnt途径刺激 |
AU2008297024B2 (en) | 2007-10-31 | 2014-08-28 | Kyoto University | Nuclear reprogramming method |
US20110151447A1 (en) | 2007-11-06 | 2011-06-23 | Children's Medical Center Corporation | Method to produce induced pluripotent stem (ips) cells from non-embryonic human cells |
US9005966B2 (en) | 2007-11-19 | 2015-04-14 | The Regents Of The University Of California | Generation of pluripotent cells from fibroblasts |
US9683232B2 (en) * | 2007-12-10 | 2017-06-20 | Kyoto University | Efficient method for nuclear reprogramming |
JP5558097B2 (ja) * | 2007-12-10 | 2014-07-23 | 国立大学法人京都大学 | 効率的な核初期化方法 |
US20090191171A1 (en) * | 2008-01-18 | 2009-07-30 | Yupo Ma | Reprogramming of Differentiated Progenitor or Somatic Cells Using Homologous Recombination |
KR101481164B1 (ko) | 2008-01-30 | 2015-01-09 | 주식회사 미래셀바이오 | 체세포 유래 다능성 줄기세포의 제조 방법 |
US20110014164A1 (en) | 2008-02-15 | 2011-01-20 | President And Fellows Of Harvard College | Efficient induction of pluripotent stem cells using small molecule compounds |
WO2009115295A1 (en) | 2008-03-17 | 2009-09-24 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Vectors and methods for generating vector-free induced pluripotent stem (ips) cells using site-specific recombination |
ES2690554T3 (es) * | 2008-03-17 | 2018-11-21 | The Scripps Research Institute | Enfoques químicos y genéticos combinados para la generación de células madre pluripotentes inducidas |
CN101250502A (zh) | 2008-04-01 | 2008-08-27 | 中国科学院上海生命科学研究院 | 一种诱导的多潜能干细胞的制备方法 |
CN101550406B (zh) * | 2008-04-03 | 2016-02-10 | 北京大学 | 制备多潜能干细胞的方法,试剂盒及用途 |
US20100021437A1 (en) * | 2008-04-07 | 2010-01-28 | The McLean Hospital Corporation Whitehead Institute for Biomedical Research | Neural stem cells derived from induced pluripotent stem cells |
US20100279404A1 (en) | 2008-05-02 | 2010-11-04 | Shinya Yamanaka | Method of nuclear reprogramming |
EP2128245A1 (en) | 2008-05-27 | 2009-12-02 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Generation of induced pluripotent stem (iPS) cells |
JP2011522540A (ja) * | 2008-06-04 | 2011-08-04 | セルラー ダイナミクス インターナショナル, インコーポレイテッド | 非ウイルスアプローチを用いたiPS細胞の産生のための方法 |
JP5553178B2 (ja) | 2008-07-31 | 2014-07-16 | 国立大学法人岐阜大学 | 効率的な人工多能性幹細胞の樹立方法 |
US20100062534A1 (en) * | 2008-09-09 | 2010-03-11 | The General Hospital Corporation | Inducible lentiviral vectors for reprogramming somatic cells |
CN105802917A (zh) | 2008-10-24 | 2016-07-27 | 威斯康星校友研究基金会 | 通过非病毒重编程获得的多潜能干细胞 |
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Non-Patent Citations (2)
Title |
---|
Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells;Taranger CK 等;《Mol Biol Cell》;20050929;第16卷(第12期);5719-35 * |
The Recent Progress on Nuclear Transfer in Mammals;Yukio Tsunoda 等;《Zoological Science》;20001231;第17卷(第9期);1177-1184 * |
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