CN110177871A - 间充质干细胞和肝疾病治疗剂 - Google Patents
间充质干细胞和肝疾病治疗剂 Download PDFInfo
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- CN110177871A CN110177871A CN201880006884.8A CN201880006884A CN110177871A CN 110177871 A CN110177871 A CN 110177871A CN 201880006884 A CN201880006884 A CN 201880006884A CN 110177871 A CN110177871 A CN 110177871A
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- liver disease
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明的目的在于提供肝疾病的新型治疗剂。本发明为间充质干细胞,其特征在于,高表达组织因子途径抑制剂(TFPI)。上述间充质干细胞优选为异体来源并且为脂肪组织来源。另外,本发明还包括含有上述间充质干细胞的肝疾病治疗剂。
Description
技术领域
本发明涉及间充质干细胞和肝疾病治疗剂。
背景技术
肝硬化是显示出显著的纤维化和再生结节形成的各种肝疾病的终结图像,在病理学上有由肝小叶重塑导致的伪小叶的形成和肝脏内和肝脏外的血流动力学异常的特征,其结果发生肝细胞功能的降低(参照非专利文献1)。在肝硬化中,还已知由于慢性的炎症而反复出现肝细胞的变性/坏死及肝脏再生,在该过程中细胞外基质被过度蓄积在肝脏内而发生纤维化。
作为肝硬化的病因,可列举出:持续感染肝炎病毒、酒精过量摄取、肥胖、胰岛素抵抗、自身免疫(原发性胆汁性肝硬化、原发性硬化性胆管炎、自身免疫性肝炎)、遗传性、药物性等(参照非专利文献2),其中,由肝炎病毒所致的肝硬化较多,特别是由丙型肝炎病毒(以下称为“HCV”)所致的比例最高。推测出HCV的载体全球存在1亿7000万人,日本国内存在150万~200万人,HCV感染者的约70%会持续感染、转变为慢性肝炎。慢性化后,病毒的自然清除低至每年0.2%,由于持续因HCV感染所致的炎症而诱发肝纤维化,并发展为肝硬化、肝细胞癌(参照非专利文献3)。
在从肝硬化的代偿期发展到伴随进一步高度的纤维化的非代偿期时,现有的药剂/治疗法就无法充分应对。因此期望开发出与现有作用机理不同的新型治疗药。
间充质干细胞是由Friedenstein(1982)首次从骨髓分离的具有多分化能力的前体细胞(参照非专利文献4)。已经明确了该间充质干细胞存在于骨髓、脐带、脂肪等各种各样的组织中,间充质干细胞移植有望成为针对各种难治性疾病的新型治疗方法(参照专利文献1~2)。最近,已知存在具有与脂肪组织、胎盘、脐带、卵膜等的基质细胞同等功能的细胞。因此,有时也将间充质干细胞称为基质细胞(Mesenchymal Stromal Cell)。
现有技术文献
专利文献
专利文献1:日本特开2012-157263号公报
专利文献2:日本特表2012-508733号公报
非专利文献
非专利文献1:渡辺明治、肝硬化病态和治疗手册、Medical Review,Inc.、2007年4月20日发行、p.12(《肝硬変病態と治療ハンドブック、メディカルレビュー社、2007年4月20日発行、p.12》)
非专利文献2:日本消化器官病学会编集、肝硬化准则2015、株式会社南江堂、2015年10月发行、P.2(《日本消化器病学会編集、肝硬変診療ガイドライン2015、株式会社南江堂、2015年10月発行、P.2》)
非专利文献3:Kiyosawa K.et.al.,Hepatology,(1990),12(4Pt 1),pp.671-675
非专利文献4:Pittenger F.M.et al.Science,(1999),284,pp.143-147
发明内容
发明要解决的问题
在上述那样的情况下,本发明的目的在于提供肝疾病的新型治疗剂。
用于解决问题的方案
为了解决上述课题而进行了深入研究,结果本发明人等发现:高表达组织因子途径抑制剂(Tissue factor pathway inhibitor:TFPI)的间充质干细胞(mesenchymal stem(stromal)cell:MSC)对于肝疾病的治疗是有效的,从而完成了本发明。根据本发明,可以提供用于治疗肝疾病有效的治疗剂。即本发明的主旨如下所述。
[1]一种间充质干细胞,其特征在于,高表达组织因子途径抑制剂(TFPI)。
[2]根据[1]所述的间充质干细胞,其为异体来源。
[3]根据[1]或[2]所述的间充质干细胞,其为脂肪组织来源。
[4]一种肝疾病治疗剂,其含有[1]~[3]中任一项所述的间充质干细胞。
[5]根据[4]所述的肝疾病治疗剂,其中,上述肝疾病为伴随肝组织的纤维化的肝疾病。
[6]一种肝疾病的治疗方法,其特征在于,其使用高表达组织因子途径抑制剂(TFPI)的间充质干细胞。
[7]根据[6]所述的肝疾病的治疗方法,其中,上述间充质干细胞为异体来源。
[8]根据[6]或[7]所述的肝疾病的治疗方法,其中,上述间充质干细胞为脂肪组织来源。
发明的效果
根据本发明,能够提供肝疾病的新型治疗剂。
附图说明
图1是示出rTFPI的、抑制肝星状细胞中的纤维化相关基因ACTA2的表达效果的图。
图2是示出rTFPI的、抑制肝星状细胞中的纤维化相关基因COL1A1的表达效果的图。
图3是示出将本发明的间充质干细胞中的TFPImRNA的表达与其它细胞进行比较的结果的图。
图4是示出将本发明的间充质干细胞中的TFPImRNA的表达与其它细胞(现有的培养条件下的间充质干细胞)进行比较的结果的图。
图5是示出将本发明的间充质干细胞中的TFPI蛋白的表达量与其它细胞(现有的培养条件下的间充质干细胞)进行比较的结果的图。
图6是示出将本发明的间充质干细胞中的TFPI蛋白的分泌量与其它细胞(现有的培养条件下的间充质干细胞)进行比较的结果的图。
图7是示出将本发明的间充质干细胞的、抑制纤维化相关基因ACTA2的表达效果与其它细胞(现有的培养条件下的间充质干细胞)进行比较的结果的图。
图8是示出将本发明的间充质干细胞的、抑制纤维化相关基因COLIA1的表达效果与其它细胞(现有的培养条件下的间充质干细胞)进行比较的结果的图。
具体实施方式
以下对本发明的间充质干细胞、肝疾病治疗剂进行详细说明。
[间充质干细胞]
本发明的间充质干细胞的特征在于高表达TFPI(Tissue factor pathwayinhibitor;组织因子途径抑制剂)。
TFPI是分子量约42000的糖蛋白,是被认为介由活性型第X因子与TF-活性型第VII因子结合并抑制其凝血活性的Kunitz型蛋白酶抑制剂[Broze,G.J.,Proc.Natl.Acad.Sci.,84,p1886(1987)]。TFPI主要在血管内皮细胞中表达且结合于细胞膜上,但已知通过凝血酶、MMPs、肝素等使结合被切断而游离。
需要说明的是,高表达TFPI包括如下情况:TFPI的mRNA表达为高表达、或TFPI蛋白为高表达、或该两者为高表达。
另外,本发明的间充质干细胞与其它细胞相比只要高表达TFPI即可,具体而言,本发明的间充质干细胞与在现有的培养条件下(例如,基于含有10%FBS的DMEM培养基的培养)得到的间充质干细胞相比只要高表达TFPI即可。优选与在现有的培养条件下得到的间充质干细胞相比表达1.5倍以上,更优选表达2倍以上,进一步优选表达3倍以上,特别优选表达5倍以上。
本发明的间充质干细胞与皮肤成纤维细胞、平滑肌细胞、上皮细胞相比只要高表达TFPI即可。优选与皮肤成纤维细胞、平滑肌细胞、上皮细胞中的任意者相比表达1.1倍以上,更优选表达1.15倍以上,进一步优选表达1.2倍以上。特别优选与皮肤成纤维细胞、平滑肌细胞、上皮细胞中的2种以上的细胞相比表达1.1倍以上、更进一步优选表达1.15倍以上、更特别优选表达1.2倍以上。进一步特别优选与皮肤成纤维细胞、平滑肌细胞、上皮细胞中的3种以上的细胞相比表达1.1倍以上、最优选表达1.15倍以上、进一步最优选表达1.2倍以上。
本发明中间充质干细胞是指:具有分化为属于间充质类的一种以上细胞(骨细胞、心肌细胞、软骨细胞、肌腱细胞、脂肪细胞等)、优选为两种以上的细胞、更优选为三种以上的细胞的分化能力,并在维持该能力的状态下能够增殖的细胞。本发明中使用的间充质干细胞的术语是指与基质细胞相同的细胞,不对两者进行特别区分。另外,有时也简记为间充质细胞。作为包含间充质干细胞的组织,例如可列举出:脂肪组织、脐带、骨髓、脐带血、子宫内膜、胎盘、羊膜、绒毛膜、蜕膜、真皮、骨骼肌、骨膜、牙囊、牙周组织、牙髓、牙胚等。例如脂肪组织来源间充质干细胞是指脂肪组织中含有的间充质干细胞,还可称为脂肪组织来源间充质干细胞。这些当中,从对肝疾病的治疗的有效性的观点、获得容易性的观点等出发,优选脂肪组织来源间充质干细胞、脐带来源间充质干细胞、骨髓来源间充质干细胞、胎盘来源间充质干细胞、牙髄来源间充质干细胞,更优选脂肪组织来源间充质干细胞、脐带来源间充质干细胞。
本发明中的间充质干细胞可以是与被处置的对象(被检体)为同种来源或异种来源。作为本发明中的间充质干细胞的种类,可列举出:人、马、牛、绵羊、猪、狗、猫、兔子、小鼠、大鼠,优选为与被处置的对象(被检体)为同种来源细胞。本发明中的间充质干细胞可以源自被处置的对象(被检体)、即为自体细胞(同种同系),或可以源自同种的其它对象、即为异体细胞(同种异体)。优选为异体细胞(同种异体)。
由于间充质干细胞对于同种异体的被检体也不易发生排斥反应,因此可以使用对预先制备的供体的细胞进行扩大培养并冷冻保存后的细胞,作为本发明的疾病治疗剂中的间充质干细胞。因此,与制备自身的间充质干细胞来使用的情况相比商品化也容易且容易稳定地得到恒定效果,从这样的观点出发,本发明中的间充质干细胞更优选为同种异体。
本发明中间充质干细胞是指:包含间充质干细胞的任意的细胞群体。该细胞群体的至少20%以上、优选30%、40%、50%、60%、70%、75%、80%、85%、90%、93%、96%、97%、98%或99%为间充质干细胞。
本发明中脂肪组织是指:含有脂肪细胞和包含微血管细胞等的基质细胞的组织,例如,是将哺乳动物的皮下脂肪外科切除或吸取哺乳动物的皮下脂肪而得到的组织。脂肪组织可以由皮下脂肪获得。优选从与后述的脂肪组织来源间充质干细胞的给药对象为同种的动物获得、考虑到对人给药,更优选为人的皮下脂肪。皮下脂肪的供给个体可以是存活或死亡的,但本发明中使用的脂肪组织优选为从存活个体采集的组织。从个体采集时,吸脂例如可示例出:PAL(动力辅助)吸脂、Erchonia激光吸脂或Body-jet吸脂等,从维持细胞的状态这样的观点出发,优选不使用超声波。
本发明中脐带是连接胎儿和胎盘的白色的管状组织,由脐带静脉、脐带动脉、胶状组织(华顿氏胶;Wharton’s Jelly)、脐带基质本身等构成,富含间充质干细胞。脐带优选从与使用本发明的疾病治疗剂的被检体(给药对象)为同种的动物获得,考虑到将本发明的疾病治疗剂对人给药,更优选为人的脐带。
本发明中骨髓是指填充骨的内腔的实质组织(parenchyma),为造血器官。骨髓中存在骨髓液,将存在于其中的细胞称为骨髓细胞。骨髓细胞中除了红细胞、粒细胞、巨核细胞、淋巴细胞、脂肪细胞等之外,包含间充质干细胞、造血干细胞、血管内皮祖细胞等。骨髓细胞例如可以由人髂骨、长骨或其它骨采集。
本发明中,所谓脂肪组织来源间充质干细胞、脐带来源间充质干细胞、骨髓来源间充质干细胞的各组织来源间充质干细胞是指:分别包含所谓脂肪组织来源间充质干细胞、脐带来源间充质干细胞、骨髓来源间充质干细胞的各组织来源间充质干细胞的任意的细胞群体。该细胞群体的至少20%以上、优选30%、40%、50%、60%、70%、75%、80%、85%、90%、93%、96%、97%、98%或99%为所谓脂肪组织来源间充质干细胞、脐带来源间充质干细胞、骨髓来源间充质干细胞的各组织来源间充质干细胞。
本发明中的间充质干细胞除了高表达上述TFPI之外,例如还可以利用生长特征(例如,从传代至老化为止的群体的倍增能力、倍增时间)、核型分析(例如,正常的核型、母体***或新生儿***)、通过流式细胞仪(例如,FACS分析)进行的表面标记物表达、免疫组织化学和/或免疫细胞化学(例如,表位检测)、基因表达谱(例如,基因芯片阵列;逆转录PCR、实时PCR、传统型PCR等聚合酶链式反应)、miRNA表达谱、蛋白质阵列、细胞因子等蛋白质分泌(例如,血浆凝血解析、ELISA、细胞因子阵列)、代谢产物(代谢组学解析)、本领域中公知的其它方法等而赋予特征。
(间充质干细胞的制备方法)
TFPI高表达的间充质干细胞的制备方法没有特别限定,例如可以如下方式进行制备。即,本领域技术人员可以依据公知的方法从脂肪组织、脐带、骨髓等组织中分离间充质干细胞并进行培养,使用与TFPI特异性结合的抗TFPI抗体,利用细胞分选仪、磁珠等将TFPI高表达细胞分离而获得。另外,通过使用了特定的培养基的培养,诱导间充质干细胞中的TFPI表达,从而还能够获得TFPI高表达的间充质干细胞。在通过该诱导而得到的细胞群体中,优选细胞群体的50%以上为TFPI高表达,更优选70%以上为TFPI高表达,进一步优选80%以上为TFPI高表达,特别优选90%以上为TFPI高表达,最优选实质上为TFPI高表达的均匀的细胞群体。以下具体地说明TFPI高表达的间充质干细胞的制备方法。
间充质干细胞可以通过本领域技术人员利用公知的方法来制备。以下作为一个例子对脂肪组织来源间充质干细胞的制备方法进行说明。脂肪组织来源间充质干细胞可以利用例如美国专利第6,777,231号中记载的制造方法得到,例如,可以利用包括以下的工序(i)~(iii)的方法来制造:
(i)通过酶消化脂肪组织而得到细胞悬浮物的工序;
(ii)使细胞沉淀,将细胞再悬浮于适合的培养基的工序;以及
(iii)在固体表面培养细胞,去除不显示出与固体表面结合的细胞的工序。
工序(i)中使用的脂肪组织优选使用经清洗的脂肪组织。清洗可以通过使用生理学允许的生理盐水溶液(例如磷酸缓冲盐水(PBS)),并剧烈地搅拌使其沉淀来进行。其原因在于,从组织中去除脂肪组织中包含的杂质(也称为残骸(debris),例如损伤组织、血液、红细胞等)。因此,通常重复进行清洗和沉淀直至从上清液中整体上去除了残骸。残留的细胞以各种各样的尺寸的块的形式存在,因此为了将细胞本身的损伤抑制在最小限度并且使其解离,而优选用使细胞间结合变弱或破坏细胞间结合的酶(例如,胶原酶、分散酶或胰蛋白酶等)对清洗后的细胞团块进行处理。这样的酶的量和处理期间依赖于所使用的条件而变化,在本技术领域中是已知的。可以替代这样的酶处理或组合地利用机械的搅拌、超声波能量、热能等其它处理法将细胞团块分解,但为了将细胞的损伤抑制在最小限度而优选仅通过酶处理进行。使用了酶的情况,为了将对细胞的有害作用抑制在最小限度,期望的是在经过适合的期间后使用培养基等使酶失活。
通过工序(i)而得到的细胞悬浮物包含聚集状的细胞的浆料或悬浮物、以及各种夹杂细胞、例如红细胞、平滑肌细胞、内皮细胞和成纤维细胞。接着,还可以分离、去除聚集状态的细胞和它们的夹杂细胞,但由于能够通过后述的工序(iii)中的粘附和清洗来去除,因此可以省略该分离、去除。在分离、去除夹杂细胞时,可以通过将细胞强制分成上清液和沉淀的离心分离来实现。将包含得到的夹杂细胞的沉淀悬浮于生理学允许的溶剂中。虽然有悬浮状的细胞中包含红细胞的担心,但由于红细胞会通过后述的由粘附于个体表面进行的选择而被排除,因此未必一定需要溶解的工序。作为选择性地溶解红细胞的方法,可以使用本技术领域中公知的方法例如通过用氯化铵溶解在高渗培养基或低渗培养基中进行孵育等。溶解后,还可以通过例如过滤、离心沉淀或密度分级从期望的细胞分离溶解物。
工序(ii)中,对于悬浮状的细胞,为了提高间充质干细胞的纯度,还可以进行1次或连续多次清洗、离心分离,并再悬浮于培养基中。此外,还可以基于细胞表面标记物图谱或基于细胞的尺寸和颗粒性对细胞进行分离。
再悬浮时使用的培养基只要是能培养间充质干细胞的培养基就没有特别限定,这样的培养基还可以通过如下方式制作:在基础培养基中添加血清、和/或添加白蛋白、运铁蛋白、脂肪酸、胰岛素、***钠、胆固醇、胶原蛋白前体、微量元素、2-巯基乙醇、3’-硫代甘油等中的1种以上的血清替代物。这些培养基还可以根据需要进一步添加脂质、氨基酸、蛋白质、多糖、维生素、生长因子、低分子化合物、抗生素、抗氧化剂、丙酮酸、缓冲剂、无机盐类等物质。
作为上述基础培养基,例如可列举出:IMDM培养基、Medium 199培养基、伊格尔最低必需培养基(Eagle’s Minimum Essential Medium,EMEM)、αMEM培养基、达尔伯克改良伊格尔培养基(Dulbecco’s modified Eagle’s Medium,DMEM)、Ham’s F12培养基、RPMI 1640培养基、Fischer’s培养基、MCDB201培养基以及它们的混合培养基等。
作为上述血清,例如可列举出:人血清、胎牛血清(FBS)、牛血清、仔牛血清、山羊血清、马血清、猪血清、绵羊血清、兔子血清、大鼠血清等,但不限定于这些。使用血清时,可以相对于基础培养基添加5v/v%~15v/v%、优选添加10v/v%。
作为上述脂肪酸,可示例出:亚油酸、油酸、亚麻酸、花生四烯酸、肉豆蔻酸、棕榈酸(palmitoyl acid)、棕榈酸(palmitic acid)和硬脂酸等,但不限定于这些。脂质可示例出:磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰胆碱等,但不限定于这些。氨基酸例如包括:L-丙氨酸、L-精氨酸、L-天冬氨酸、L-天冬酰胺、L-半胱氨酸、L-胱氨酸、L-谷氨酸、L-谷氨酰胺、L-甘氨酸等,但不限定于这些。蛋白质例如可示例出:大肠杆菌素、还原型谷胱甘肽、纤维连接蛋白和β2-微球蛋白等,但不限定于这些。多糖可示例出糖胺聚糖,糖胺聚糖中尤其可示例出透明质酸、硫酸乙酰肝素等,但不限定于这些。生长因子例如可示例出:血小板来源生长因子(PDGF)、碱性成纤维细胞生长因子(bFGF)、转化生长因子β(TGF-β)、肝细胞生长因子(HGF)、表皮生长因子(EGF)、***生长因子(CTGF)、血管内皮细胞生长因子(VEGF)等,但不限定于这些。从将本发明中得到的脂肪来源间充质干细胞用于细胞移植这样的观点出发,优选使用血清等不包含异种来源成分(无异源,xeno-free)的培养基。这样的培养基例如以由PromoCell公司、Lonza公司、Biological Industries公司、Veritas公司、R&DSystems公司、Corning公司和Rohto公司等作为间充质干细胞(基质细胞)用预先制备的培养基的形式提供。
接着,工序(iii)中,对于工序(ii)中得到的细胞悬浮液中的细胞,不使之分化而在固体表面上、在适合的细胞密度和培养条件下使用上述的适合的细胞培养基对其进行培养。本发明中,“固体表面”是指:能够结合/粘附本发明中的脂肪组织来源间充质干细胞的任意材料。在特定的方式中,这样的材料是为了促进哺乳类细胞与该表面的结合/粘附而经处理的塑料材料。具有固体表面的培养容器的形状没有特别限定,可适宜地使用培养皿、烧瓶等。为了去除非结合状态的细胞和细胞的碎片,在孵育后清洗细胞。
本发明中,可以选择最终以与固体表面结合/粘附的状态滞留的细胞作为脂肪组织来源间充质干细胞的细胞群体。
对于所选择的细胞,为了确认为本发明中的脂肪组织来源间充质干细胞,还可以使用流式细胞仪等利用现有的方法对表面抗原进行解析。进而,还可以对分化为各细胞系列的能力进行检测,这样的分化可以利用现有的方法进行。
本发明中的间充质干细胞可以如上所述进行制备,但还可以定义为具有以下特性的细胞;
(1)在标准培养基中的培养条件下,对塑料显示出粘附性、
(2)表面抗原CD44、CD73、CD90为阳性,CD31、CD45为阴性、和
(3)在培养条件下能分化为骨细胞、脂肪细胞、软骨细胞。
利用使用了细胞分选仪、磁珠等的免疫学方法从通过上述工序(iii)而得到的间充质干细胞中选择性地分离高表达了TFPI蛋白的细胞,由此能够获得高表达了TFPI蛋白的间充质干细胞。另外,通过进行基于能够诱导TFPI的表达的特定培养基的培养,从而还能够诱导间充质干细胞中的TFPI表达,有效地获得TFPI高表达的间充质干细胞。作为一个例子,以下对基于使用了细胞分选仪的免疫学方法进行的选择性分离的具体的方法进行说明。
将通过胰蛋白酶·EDTA溶液等对上述制备的间充质干细胞进行处理而得到的细胞悬浮液离心分离(室温、400G、5分钟)并去除上清液。向细胞中加入染色缓冲液(1%BSA-PBS),制成1×106个细胞/500uL,通过移液使细胞悬浮液浓度均匀后,分注在新的1.5mL微型管中各50uL。在分注的细胞悬浮液中以5~20μg/mL的浓度添加初级抗体(小鼠抗人TFPI、Sekisui diagnostics公司制、ADG4903)使其悬浮后,在遮光/冷藏下反应30分钟~1小时。用染色缓冲液(Staining Buffer)1mL进行3次清洗后,加入染色缓冲液制成50uL,以1~10μg/mL的浓度添加二级抗体(Anti Mouse IgG alexar488、Thermofisher scientific公司制、A21202)使其悬浮后,在遮光/冷藏下反应30分钟~1小时。用染色缓冲液1mL进行3次清洗后,加入PI缓冲液(在染色缓冲液14.4mL中添加碘化丙啶溶液(SIGMA公司制、P4864)28.8μL来制备)300uL并充分悬浮,通过带细胞滤网的管,用荧光激活细胞分选***(fluorescence activated cell sorting,FACS)进行分离。
(间充质干细胞的冷冻保存)
本发明中的间充质干细胞只要具备疾病治疗效果就可以是适宜重复进行了冷冻保存和融解的细胞。本发明中,冷冻保存可以通过如下方式进行:本领域技术人员将间充质干细胞悬浮于公知的冷冻保存液中进行冷却。悬浮可以通过如下方式进行:利用胰蛋白酶等剥离剂使细胞剥离,转移至冷冻保存容器中进行适宜处理后,加入冷冻保存液。
冷冻保存液作为冷冻保护剂还可以含有二甲基亚砜(DMSO:Dimethylsulfoxide),但DMSO除了细胞毒性之外还具有分化诱导间充质干细胞的特性,因此优选减少DMSO含量。作为DMSO的替代物,可示例出:甘油、丙二醇或多糖类。使用DMSO时,含有5%~20%的浓度、优选含有5%~10%的浓度、更优选含有10%的浓度。此外还可以包含WO2007/058308中记载的添加剂。作为这样的冷冻保存液,例如还可以使用由Bioverde Inc.、NIPPON Genetics Co,Ltd.、REPROCELL Inc.、ZENOAQ公司、Cosmo Bio Co.,Ltd.、KohjinBio Co.,Ltd.、Thermo Fisher Scientific Inc.等提供的冷冻保存液。
冷冻保存上述悬浮的细胞时,在-80℃~-100℃之间的温度(例如,-80℃)下保管为宜,可以使用能达到该温度的任意的冷冻仪来进行。没有特别限定,为了避免急剧的温度变化,还可以使用程序冷冻仪来适宜控制冷却速度。冷却速度可以根据冷冻保存液的成分进行适宜选择,可以依据冷冻保存液的制造者指示来进行。
保存期间只要在上述条件下经冷冻保存的细胞融解后保持与冷冻前同等性质就没有特别限定,例如可列举出:1周以上、2周以上、3周以上、4周以上、2个月以上、3个月以上、4个月以上、5个月以上、6个月以上、1年以上或更长时间。通过在更低的温度下保存而能够抑制细胞毒性,因此还可以移至液氮上的气相(从-180℃以上至约-150℃以下)中进行保存。在液氮上的气相中保存时,可以使用本领域技术人员公知的保存容器来进行。没有特别限定,例如保存2周以上时,优选在液氮上的气相中进行保存。
融解的间充质干细胞在下次冷冻保存前,还可以适宜地进行培养。间充质干细胞的培养使用能培养上述的间充质干细胞的培养基进行,没有特别限定,还可以在30~40℃、优选为在约37℃的培养温度下、在含有CO2的空气气氛下进行。CO2浓度为约2~5%、优选为约5%。在培养时,在相对于培养容器到达适合的汇合(例如可列举出相对于培养容器,细胞占50%至80%的情况)后,还可以用胰蛋白酶等剥离剂使细胞剥离,以适合的细胞密度接种于另行准备的培养容器中继续进行培养。在接种细胞时,作为典型的细胞密度,可示例出:100细胞/cm2~100000细胞/cm2、500细胞/cm2~50000细胞/cm2、1000~10000细胞/cm2、2000~10000细胞/cm2等。在特定的方式中,细胞密度为2000~10000细胞/cm2。优选为3天~7天到达适合的汇合的方式进行调节。在培养时,还可以根据需要适宜更换培养基。
经冷冻保存的细胞的融解可以通过本领域技术人员利用公知的方法来进行。例如可示例出通过在37℃的恒温槽内或热水浴中静置或振荡来进行的方法。
本发明的间充质干细胞可以是任意状态的细胞,例如可以是将培养中的细胞剥离并回收的细胞,还可以是在冷冻保存液中被冷冻的状态的细胞。使用将扩大培养而得到的相同批次的细胞分成小部分进行冷冻保存后的细胞时,在稳定地得到同样的作用效果方面、操作性优异方面等是优选的。冷冻保存状态的间充质干细胞可以在即将使用之前进行融解并悬浮于冷冻保存液的状态下直接混合于输液或培养基等的溶液中。另外,可以利用离心分离等方法去除冷冻保存液后悬浮于输液或培养基等的溶液中。此处,本发明中的“输液”是指:对人进行治疗时所使用的溶液,没有特别限定,溶液例如可列举出:生理盐水、日本药典生理盐水、5%葡萄糖液、日本药典葡萄糖注射液、林格氏液、日本药典林格溶液、乳酸林格氏液、乙酸林格氏液、1号液(初始溶液)、2号液(脱水补充剂)、3号液(维持液)、4号液(术后恢复液)等。
[肝疾病治疗剂]
本发明的肝疾病治疗剂含有上述的本发明的TFPI高表达的间充质干细胞。通过本发明的肝疾病治疗剂,能够有效地抑制肝脏的纤维化。对于本发明的肝疾病治疗剂所包含的间充质干细胞,可以适用上述间充质干细胞项目中的说明。
本发明的肝疾病治疗剂只要在不损害本发明的效果的范围内,除了上述间充质干细胞以外还可以根据其用途、形态,按照常规方法含有药学上可接受的载体、添加物。作为这样的载体、添加物,例如可列举出:等渗剂、增稠剂、糖类、糖醇类、防腐剂(保存剂)、杀菌剂或抗菌剂、pH调节剂、稳定化剂、螯合剂、油性基质、凝胶基质、表面活性剂、悬浮化剂、粘结剂、赋形剂、润滑剂、崩解剂、发泡剂、流动化剂、分散剂、乳化剂、缓冲剂、助溶剂、抗氧化剂、甜味剂、酸味剂、着色剂、呈味剂、香料或清凉化剂等,但不限定于这些。作为代表性的成分,例如可列举出以下的载体、添加物等。
作为载体,例如可列举出:水、含水乙醇等的水性载体;作为等渗剂(无机盐),例如可列举出:氯化钠、氯化钾、氯化钙、氯化镁等;作为多元醇,例如可列举出:甘油、丙二醇、聚乙二醇等;作为增稠剂,例如可列举出:羧乙烯基聚合物、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、藻酸、聚乙烯醇(完全、或部分皂化物)、聚乙烯基吡咯烷酮、聚乙二醇等;作为糖类,例如可列举出:环糊精、葡萄糖等;作为糖醇类,例如可列举出:木糖醇、山梨醇、甘露糖醇等(它们可以是d构型、l构型或dl构型中的任意者);作为防腐剂、杀菌剂或抗菌剂,例如可列举出:二丁基羟基甲苯、丁基羟基茴香醚、烷基二氨基乙基甘氨酸盐酸盐、苯甲酸钠、乙醇、苯扎氯铵、苄索氯铵、葡萄糖酸洗必泰、氯丁醇、山梨酸、山梨酸钾、氨丁三醇、脱氢醋酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、羟基喹啉硫酸盐、苯乙醇、苄醇、双胍化合物(具体而言,聚己缩胍盐酸盐(聚六亚甲基双胍盐酸盐)等)、Glokill(Rhodia公司制商品名)等;作为pH调节剂,例如可列举出:盐酸、硼酸、氨基乙基磺酸、ε-氨基己酸、柠檬酸、乙酸、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸氢钠、碳酸钠、硼砂、三乙醇胺、单乙醇胺、二异丙醇胺、硫酸、硫酸镁、磷酸、多聚磷酸、丙酸、草酸、葡萄糖酸、富马酸、乳酸、酒石酸、苹果酸、琥珀酸、葡萄糖酸内酯、乙酸铵等;作为稳定化剂,例如可列举出:二丁基羟基甲苯、氨丁三醇、甲醛次硫酸氢钠(RONGALIT)、生育酚、焦亚硫酸钠、单乙醇胺、单硬脂酸铝、单硬脂酸甘油酯、亚硫酸氢钠、亚硫酸钠等;作为油性基质,例如可列举出:橄榄油、玉米油、大豆油、芝麻油、棉籽油等植物油、中链脂肪酸甘油三酯等;作为水性基质,例如可列举出:聚乙二醇400等;作为凝胶基质,例如可列举出:羧乙烯基聚合物、胶质等;作为表面活性剂,例如可列举出:聚山梨醇酯80、氢化蓖麻油、脂肪酸甘油酯、山梨坦倍半油酸酯等;作为悬浮化剂,例如可列举出:白蜂蜡、各种表面活性剂、***胶、***胶粉末、黄原胶、大豆磷脂等;作为粘结剂,例如可列举出:羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯基吡咯烷酮、聚乙烯醇等;作为赋形剂,例如可列举出:蔗糖、乳糖、淀粉、玉米淀粉、结晶纤维素、轻质硅酸酐等;作为润滑剂,例如可列举出:蔗糖脂肪酸酯、硬脂酸镁、滑石等;作为崩解剂,例如可列举出:低取代度羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠等;作为发泡剂,例如可列举出:碳酸氢钠等;作为流动化剂,例如可列举出:偏硅酸铝钠、轻质硅酸酐等。
本发明的肝疾病治疗剂根据目的可以以各种形态、例如固体制剂、半固体制剂、液体制剂等各种各样的剂型来提供。例如可以以固体制剂(片剂、粉末、散剂、颗粒剂、胶囊剂等)、半固体制剂[软膏剂(硬软膏剂、软软膏剂等)、霜剂等]、液体制剂[洗剂、萃取剂、悬浮剂、乳剂、糖浆剂、注射剂(包括输液剂、嵌入式注射剂、缓释型注射、使用时制备型的注射剂)、透析用剂、气雾剂、软胶囊剂、营养剂等]、贴剂、巴布剂等的形态加以利用。另外,本发明的肝疾病治疗剂还可以以油性或水性的赋形剂中的溶液或乳液等的形式加以利用。进而,本发明的肝疾病治疗剂还可以通过喷雾来用于患部,本发明的肝疾病治疗剂还可以以喷雾后在患部被凝胶化或片化的形态加以利用。本发明的肝疾病治疗剂还可以在将上述间充质干细胞制成片状或立体结构体后用于患部。
对于本发明的肝疾病治疗剂,可以使用生理盐水、日本药典生理盐水、5%葡萄糖液、日本药典葡萄糖注射液、林格氏液、日本药典林格氏液、乳酸林格氏液、乙酸林格氏液、碳酸氢盐林格氏液、1号液(初始溶液)、2号液(脱水补给液)、3号液(维持液)、4号液(术后恢复液)等输液、或DMEM等细胞培养培养基进行悬浮或稀释来使用,优选用生理盐水、5%葡萄糖液、1号液(初始溶液)、更优选用5%葡萄糖液、1号液(初始溶液)进行悬浮或稀释来使用。
本发明的肝疾病治疗剂为液体制剂时,肝疾病治疗剂的pH只要在药物上、药理学上(制药上)或生理学上可接受的范围内就没有特别限定,作为一个例子,可列举出为2.5~9.0、优选为3.0~8.5、更优选为3.5~8.0的范围。
本发明的肝疾病治疗剂为液体制剂时,对于肝疾病治疗剂的渗透压,只要在生物体可接受的范围内就没有特别限制。作为本发明的组合物的渗透压比的一个例子,可列举出优选为0.7~5.0、更优选为0.8~3.0、进一步优选为0.9~1.4的范围。渗透压的调节可以使用无机盐、多元醇、糖醇、糖类等,利用该技术领域中已知的方法进行。渗透压比是基于第十五次修订日本药典、试样的渗透压相对于286mOsm(0.9w/v%氯化钠水溶液)的渗透压之比,渗透压参考日本药典中记载的渗透压测定法(冰点下降法)进行测定。需要说明的是,对于渗透压比测定用标准液(0.9w/v%氯化钠水溶液),可以如下制备:将氯化钠(日本药典标准试剂)在500~650℃下干燥40~50分钟后,在干燥器(硅胶)中进行自然冷却,准确称量其0.900g,溶解于纯化水中准确地制成100mL,或使用市售的渗透压比测定用标准液(0.9w/v%氯化钠水溶液)。
本发明的肝疾病治疗剂向对象的给药途径可列举出:口服给药、皮下给药、肌肉给药、静脉内给药、动脉内给药、髄腔内给药、腹腔内给药、舌下给药、直肠给药、***给药、眼内给药、经鼻给药、吸入、经皮给药、植入物、向肝表面的喷雾及通过片等的粘贴进行的直接给药等,从发明的肝疾病治疗剂的的有效性的观点出发,优选为植入物、肝动脉内给药、静脉内给药和向肝表面的喷雾和通过片等的粘贴进行的直接给药,从减轻对象者的负担的观点出发,更优选为静脉内给药。
本发明的肝疾病治疗剂中,其用量(给药量)可以根据患者的状态(体重、年龄、症状、身体状况等)及本发明的肝疾病治疗剂的剂型等而不同,从发挥充分的肝疾病治疗剂的治疗效果的观点出发,有优选大量的倾向,另一方面,从抑制副作用的表现的观点出发,有优选小量的倾向。通常,在对成人给药时,作为细胞数,为1×103~1×1012个/次、优选为1×104~1×1011个/次、更优选为1×105~1×1010个/次、进一步优选为5×106~1×109个/次。另外,作为患者的单位体重的给药量,为1×10~5×1010个/kg、优选为1×102~5×109个/kg、更优选为1×103~5×108个/kg、进一步优选为1×104~5×107个/kg的。需要说明的是,可以将本用量作为1次量来进行多次给药,还可以将本用量分成多次进行给药。
本发明的肝疾病治疗剂可以与1种或2种以上的其它药剂一起给药。作为其它药剂,可列举出可以作为肝脏的治疗药使用的任意药剂,例如可列举出:乙型肝炎治疗药(拉米夫定(Lamivudine)、阿德福韦(Adefovir)、恩替卡韦(Entecavir)、替诺福韦(Tenofovir)等)、干扰素制剂(干扰素α、干扰素α-2b、干扰素β、PEG干扰素α-2a、PEG干扰素α-2b等)、丙型肝炎治疗药(利巴韦林(Ribavirin)、特拉匹韦(Telaprevir)、司美匹韦(simeprevir)、伐尼瑞韦(Vaniprevir)、达卡他韦(Daclatasvir)、阿那匹韦(Asunaprevir)、索非布韦(Sofosbuvir)等)、糖皮质激素(***龙(Prednisolone)、甲基***龙琥珀酸钠等)、抗凝固剂(干燥浓缩人抗凝血酶III、甲磺酸加贝酯(Gabexate Mesilate)、血栓调节蛋白α等)、解毒剂(依地酸钙二钠水合物、谷胱甘肽(Glutathione)、2,3-二巯基-1-丙醇、硫代硫酸钠水合物、舒更葡糖钠(Sugamadex sodium)等)、人血清白蛋白、肝脏提取物、熊去氧胆酸、甘草酸、硫唑嘌呤、苯扎贝特(Bezafibrate)、氨基酸(甘氨酸、L-半胱氨酸、L-异亮氨酸、L-亮氨酸、L-缬氨酸、L-苏氨酸、L-丝氨酸、L-丙氨酸、L-蛋氨酸、L-苯丙氨酸、L-色氨酸、L-赖氨酸、L-组氨酸、L-精氨酸和它们的盐等)、维生素(生育酚、黄素腺嘌呤二核苷酸、硫胺素二硫化物磷酸盐(Thiamine disulfide phosphate)、吡哆醇(Pyridoxine)、维生素B12(Cyanocobalamin)和它们的盐等)、抗生素(舒巴坦钠(Sulbactam sodium)、头孢哌酮钠(Cefoperazone sodium)、美洛培南(Meropenem)水合物、盐酸万古霉素(Vancomycinhydrochloride)等)等。
本发明的间充质干细胞可以用于各种各样的肝疾病、肝损伤,作为具体的疾病,可列举出:自身免疫性肝炎、重型肝炎、慢性肝炎、病毒性肝炎、酒精性肝炎、非酒精性脂肪性肝疾病(nonalcoholic fatty liver disease(NAFLD))、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis(NASH))、非酒精性脂肪性肝(nonalcoholic fattyliver(NAFL))、肝纤维化、肝硬化、肝癌、脂肪肝、药剂过敏性肝损伤、血色沉着病、含铁血黄素沉着症、血铜蓝蛋白缺乏症、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、胆道闭锁、肝脓疡溃、慢性活动性肝炎、慢性持续性肝炎等肝疾病。其中,由于本发明的间充质干细胞具有纤维化抑制效果,因此可以适宜地用于肝纤维化、肝硬化等伴随肝组织的纤维化的疾病。
<肝疾病的治疗方法>
根据本发明的另一方案,本发明还包括肝疾病的治疗方法,其特征在于,使用高表达组织因子途径抑制剂(TFPI)的间充质干细胞。即,根据本发明,通过对肝疾病的患者给予高表达组织因子途径抑制剂(TFPI)的间充质干细胞,从而能够治疗、改善肝疾病、特别是伴随纤维化的肝疾病。需要说明的是,对于用于本发明的治疗方法的间充质干细胞,可以适用上述的[间充质干细胞]项目和[肝疾病治疗剂]项目中的说明。
实施例
以下列举实施例和试验例对本发明进行详细地说明,但本发明不受这些实施例等限定。
1.针对rTFPI的人肝星状细胞株的纤维化抑制效果的研究
[人肝星状细胞株的培养]
将经冷冻保存的人肝星状细胞株(Human Hepatic Stellate Cells(HHSteC)、ScienCell Research Laboratories公司制、产品编号:5300)的细胞悬浮液浸渍于37℃的恒温槽中使其融解。向融解的HHSteC悬浮液中加入星状细胞培养基(Stellate CellMedium)(ScienCell Research Laboratories公司制、产品编号:5301)使总量为2mL,分取出HHSteC悬浮液15μL,与等量的台盼蓝溶液(0.4%)混合并测量了活细胞数和死细胞数。在新的15mL离心管(Sumitomo Bakelite Co.,Ltd.制)中分取接种所需的细胞悬浮液量。向分取的HHSteC悬浮液中加入星状细胞培养基使总量为30mL,在3张多聚-L-赖氨酸涂层(POLY-L-Lysine coated)100mm培养皿(以下,“100mm dish”、IWAKI公司制、产品编号:4020-040)中每孔各接种10mL。将接种了细胞的100mm dish放入CO2孵化器内(37℃、5%CO2)中,1天后用新的星状细胞培养基进行培养基更换,继续进行培养。在接种HHSteC后第4天从100mmdish中去除培养基,用PBS 10mL清洗培养皿内。去除PBS后,向100mm dish中加入StemProAccutase Cell Dissociation Reagent(Thermo Fisher Scientific公司制、A11105-01、Lot.1750154)各2mL,在CO2孵化器内孵育5分钟。将HHSteC悬浮液移至50mL离心管后,向各100mm dish中加入星状细胞培养基10mL,将残留的HHSteC回收至同一50mL离心管中,以室温、300×g进行5分钟离心(Eppendorf公司制、5702)。去除上清液,将HHSteC再悬浮于星状细胞培养基10mL中,分取出15μL,与等量的台盼蓝溶液(0.4%)混合并测量了活细胞数和死细胞数。计算出接种所需的细胞悬浮液量后,用星状细胞培养基进行定容,以浓度为7.6×104个细胞/mL的方式制备了HHSteC悬浮液。以每1孔各1mL(7.6×104细胞)的方式将HHSteC接种在多聚-l-赖氨酸涂层的12孔板(以下、“12孔板”、IWAKI公司制、产品编号:4815-040)中,放入CO2孵化器(37℃、5%CO2)内开始进行培养。
[通过rTFPI的纤维化相关基因表达的抑制]
自开始培养起1天后,从CO2孵化器中取出接种了HHSteC的12孔板。将对应于组编号1的孔的培养基去除,添加星状细胞培养基1mL(对照组)。将对应于组编号2的孔的培养基去除,添加了重组TFPI(R&D Systems公司制、2974-PI-010)1ng/mL和星状细胞培养基(TFPI1ng/mL添加组)。去除对应于组编号3的孔的培养基,添加了重组TFPI 1000ng/mL和星状细胞培养基(TFPI 1000ng/mL添加组)。放入CO2孵育器中培养一天后,回收HHSteC的总RNA,利用定量PCR测定了作为纤维化相关因子的ACTA2和COL1A1的mRNA表达量。引物使用下述表中记载的物质。将结果示于图1的(ACTA2)和图2(COL1A1)。
[表1]
如图1和图2所示,HHSteC中的ACTA2和COL1A1的mRNA表达通过rTFPI处理而被抑制。
2.各种细胞株中的TFPI表达量的比较
在6孔板(Corning,#3335)中以5000个细胞/cm2接种人脂肪来源间充质干细胞(L-ADSC、Lonza公司制)、人皮肤成纤维细胞(hDFa、Human Dermal Fibroblasts,成人ThermoFisher Scientific公司制)、人大动脉平滑肌细胞(hASMS、Human Aortic Smooth MuscleCells、Thermo Fisher Scientific公司制)、Hela细胞(Hela公司制),用作为适于各细胞的培养基的间充质干细胞用无血清培养基(Rohto公司)、Cascade Biologics Medium106+LSGS(Thermo Fisher Scientific,#M-106-500)、10%FBS DMEM培养基(Sigma,#D5796)、平滑肌细胞生长培养基(promocell,#C-22062)进行3天培养,然后回收总RNA,利用定量PCR确认了TFPI的mRNA表达。引物使用下述表中记载的物质(实时PCR用商用引物(EurofinsGenomics Inc.制))。将结果示于图3。
[表2]
如图3所示,可知用Rohto公司的培养基培养的间充质干细胞与其它细胞(人皮肤成纤维细胞(hDFa)、人大动脉平滑肌细胞(hASMS)、Hela细胞)相比,TFPI的mRNA为高表达。具体而言,用Rohto公司的培养基培养的间充质干细胞中的TFPI的mRNA的表达是相对于hDFa为1.34倍,相对于hASMS为1.65倍,相对于Hela细胞为2.14倍的高表达。
3.脂肪来源间充质干细胞的TFPI表达的增强
[脂肪来源间充质干细胞的制备]
获得人供体的同意后,用生理盐水清洗利用吸脂法得到的皮下脂肪组织。为了实现细胞外基质的破坏和细胞的分离,添加胶原酶(Roche diagnostics公司)(溶剂为生理盐水),在37℃下振荡90分钟使其分散。接着,将该上述悬浮液以800g进行5分钟离心分离而得到间质血管细胞群的沉淀。在上述细胞的沉淀中加入间充质干细胞用无血清培养基(Rohto公司),将该细胞悬浮液以400g进行5分钟离心分离,去除上清液后再悬浮于间充质干细胞用无血清培养基(Rohto公司)中,将细胞接种于烧瓶中。将细胞在37℃下5%CO2中培养数天。数天后用PBS清洗培养物来去除培养液中包含的血球、脂肪组织的残留等,得到粘附于塑料容器中的间充质干细胞。
[细胞表面标记物的解析(流式细胞仪)]
利用流式细胞仪实施了脂肪组织来源间充质干细胞上的各种表面标记物的评价。将脂肪组织来源间充质干细胞再悬浮于FACS染色用缓冲剂中。用于FACS分析的抗体为FITC(异硫氰酸荧光素)或PE(藻红蛋白)标识的小鼠抗人抗体CD45、CD73、CD90和对应的小鼠IgG1同型对照抗体。细胞在室温下进行30分钟染色,接着进行清洗,使用BDFADSCantoII(BDBiosciences、San Jose、CA)进行解析。数据使用BD FACSDiva SoftwCre(BD Biosciences)进行分析。其结果,脂肪组织来源间充质干细胞(以下“ADSC”)对CD45呈阴性,对CD73、CD90呈阳性。
[脂肪组织来源间充质干细胞的冷冻保存]
使用胰蛋白酶将得到的ADSC剥离并移至离心管中,以400×g进行5分钟离心分离而得到细胞的沉淀。去除上清液后加入适量细胞冷冻保存液(STEM-CELLBANKER(ZENOAQ公司))使其悬浮。将该细胞悬浮溶液分注于内旋盖冷冻管中后,在冷冻仪内以-80℃保存,然后转移至液氮上的气相中继续进行保存。
[脂肪来源间充质干细胞的TFPI表达的增强]
从P2至P4分别用间充质干细胞用无血清培养基(Rohto公司)、ProAD(Procal;Rohto公司制)、无血清培养基(Lonza公司制)、10%FBS血清培养基培养ADSC制作了冷冻储存物。将各P4细胞复苏,以5000个细胞/cm2接种在6孔板中,分别用4种培养基各培养3天后,回收了总RNA、蛋白质、培养上清液。分别使用定量PCR(图4)和印迹法(图5)检测了TFPI的mRNA表达和蛋白质表达。使用人TFPI Quantikine ELISA Kit(R&D systems,#DTFP10)测定了培养上清液中的TFPI浓度(图6)。
可知:与10%FBS血清培养基相比,在任意的无血清培养基中,TFPI的mRNA表达量(图4)和TFPI的蛋白表达(图5)均显著地高。另外,如图6所示,可知:与10%FBS血清培养基相比,在任意的无血清培养基中,在培养上清液中分泌的TFPI量均显著地高。具体而言,用Rohto公司的间充质干细胞用无血清培养基培养的间充质干细胞中的TFPI的mRNA的表达是与用Procal培养基培养的情况相比为1.16倍,与用Lonza公司培养基培养的情况相比为2.64倍,与用10%FBS血清培养基培养的情况相比为6.92倍的高表达。另外,对于在培养上清液中分泌的TFPI量,在Rohto公司的间充质干细胞用无血清培养基的培养上清液中分泌的TFPI量(pg/mL),与在Procal培养基中的培养上清液相比为2.54倍,与在Lonza公司培养基中的培养上清液相比为5.43倍,与在10%FBS血清培养基中的培养上清液相比为5.83倍。
4.脂肪来源间充质干细胞的抗纤维化活性的增强
与上述3同样地,从P2至P4分别用间充质干细胞用无血清培养基(Rohto公司)、Lonza公司制无血清培养基(Lonza公司制)、10%FBS血清培养基培养ADSC,制作了冷冻储存物。
将经冷冻保存的ADSC浸渍于37℃的恒温槽中使细胞悬浮液融解后,分取至15mL离心管中,分别用间充质干细胞用无血清培养基(Rohto公司)、无血清培养基(Lonza公司制)、10%FBS血清培养基定容至10mL,以室温、400×g进行5分钟离心(Eppendorf公司制、5702)。离心后去除上清液,加入各培养基6mL,分取出细胞悬浮液15μL,与等量的台盼蓝溶液(0.4%)混合并测量了活细胞数和死细胞数。在新的15mL离心管中分取接种所需的细胞,加入各培养基,制成活细胞浓度为1.52×104个细胞/mL。在12孔板的各孔上设置transwell***物(corning、#3460),在下部隔室中加入各培养基1mL,在transwell***物中各加入0.5mL的以活细胞浓度1.52×104个细胞/mL调节的各ADSC,接种了细胞。放入CO2孵化器(37℃、5%CO2)内,开始进行培养。自开始培养起1天后从CO2孵化器(37℃、5%CO2)中取出接种了细胞的板,去除下部隔室内的培养基,用PBS 1mL清洗后去除PBS,加入星状细胞培养基1mL。去除各transwell***物内的培养基,用PBS 0.5mL进行2次清洗后去除PBS,加入星状细胞培养基0.5mL。
与上述1同样地,从CO2孵化器中取出接种HHSteC并培养了1天的12孔板,去除各孔的培养基后加入星状细胞培养基1mL。在对应于组编号1(对照组)的孔上设置空的transwell***物,加入星状细胞培养基0.5mL。在对应于组编号2~4的孔上设置接种了分别在间充质干细胞用无血清培养基(Rohto公司、Rohto群)、无血清培养基(Lonza公司制、Lonza群)、10%FBS血清培养基(10%FBS群)中培养的ADSC的transwell***物。将设置有transwell***物的板放入CO2孵化器(37℃、5%CO2)内,开始进行HHSteC与ADSC的共培养。自开始共培养起1天后回收HHSteC的总RNA,利用定量PCR测定了作为纤维化相关因子的ACTA2和COL1A1的mRNA表达量。将结果示于图7(ACTA2)和图8(COL1A1)。
HHSteC中的ACTA2和COL1A1的mRNA的表达通过与ADSC的共培养而被显著地抑制。另外,对于抑制效果确认了,与用血清培养基培养的ADSC相比,用间充质干细胞用无血清培养基(Rohto公司)培养的ADSC显著高。
产业上的可利用性
通过本发明,可提供新型的间充质干细胞和含有其的肝疾病治疗剂。
序列表
<110> 日本乐敦制药株式会社(ROHTO Pharmaceutical Co.,Ltd.)
<120> 间充质干细胞和肝疾病治疗剂
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Claims (5)
1.一种间充质干细胞,其特征在于,高表达组织因子途径抑制剂(TFPI)。
2.根据权利要求1所述的间充质干细胞,其为异体来源。
3.根据权利要求1或2所述的间充质干细胞,其为脂肪组织来源。
4.一种肝疾病治疗剂,其含有权利要求1~3中任一项所述的间充质干细胞。
5.根据权利要求4所述的肝疾病治疗剂,其中,上述肝疾病为伴随肝组织的纤维化的肝疾病。
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