CN117398427B - 包含iPS诱导定向分化成心肌细胞的药物组合在用于治疗心力衰竭中的应用 - Google Patents
包含iPS诱导定向分化成心肌细胞的药物组合在用于治疗心力衰竭中的应用 Download PDFInfo
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Abstract
本发明涉及包含iPS诱导定向分化成心肌细胞的药物组合在用于治疗心力衰竭中的应用。所述应用能够有效的治疗心力衰竭，进一步的将所述的诱导分化获得的心肌细胞与丹参注射液一起使用后具有较好的治疗心肌梗死的效果，将二者组合使用后可以有效地用于制备心力衰竭的药物组合，应用前景较好。
Description
技术领域
本申请涉及生物领域，具体的涉及包含iPS诱导定向分化成心肌细胞的药物组合在用于治疗心力衰竭中的应用。
背景技术
iPS细胞不仅在细胞形态、生长特性、干细胞标志物表达等方面与ES细胞非常相近，而且在DNA甲基化方式、基因表达谱、染色质状态、形成嵌合体动物等方面也与ES细胞几乎完全相同，其自我更新能力较强，且具有高度的分化能力。目前，iPS细胞可在体外被诱导生成所有210种构成人体的细胞，具有无限的疾病治疗前景。理论上，iPS细胞培养出的组织或器官移植回原患者身体内时，可避开自身免疫***的攻击难题，同时以往ES细胞所产生的道德伦理问题也可以取得根本解决。因此，iPS细胞成为了再生医学中备受瞩目的重要细胞来源。干细胞技术颠覆了医学治疗的思路，未来的治病的药物，将不再是各种的化学合成物，而是秉持着细胞的问题细胞解决，把像是小分子蛋白、抗体、干细胞等具有活性的物质送到体内，进而治疗疾病。诱导性多能干细胞（iPS干细胞），它的作用能分化与构成身体各种细胞，它能在极少量的皮肤碎片或血液中制造出来。日本干细胞科学家山中伸弥正是因为成功将成年细胞逆转为iPS细胞，于2012年得到了诺贝尔生医奖的殊荣。
目前iPS治疗是非常热门的干细胞种类，包括了眼角膜移植、帕金森氏症、黄斑部退化、心脏疾病、脊髓疾病、输血性疾病、关节炎、第一型糖尿病以及白血病等9 种疾病，在未来几年就有机会使用iPS干细胞在临床治疗。
近年来，IPS细胞的应用在治疗严重慢性缺血性心力衰竭领域取得了一些进展。日本大阪大学(Osaka University)心血管外科的一个研究团队,采用诱导的多潜能干细胞（IPS）治疗缺血性心肌病的临床治疗研究, 近日获得日本监管机构的有条件批准。国际上采用IPS临床应用的实验研究为数并不多,而日本处于领先位置。近年来，以日本RIKEN研究所的高桥雅代(Masayo Takahashi)博士领导的团队，首先开始采用IPS细胞，在眼科黄斑变性的患者中进行临床研究。以往，心力衰竭的细胞治疗多采用：骨髓细胞，血管内皮前体细胞，骨骼肌细胞，间充质干细胞或心脏干细胞。日本大阪大学宣布，已成功为心脏功能不全患者移植了心肌薄膜，而该薄膜正是利用iPS细胞培养出来的。简单来说，未来有重度心肌梗塞甚至心衰竭的病人，不用仰赖人工心脏或是等不到的器官捐赠，用干细胞就可以救回心脏。IPS诱导分化的心肌细胞在心脏病患者中的使用，还是首次创新性工作。
我国自主研发的“人iPSC来源心肌细胞注射液”产品（HiCM-188）临床试验申请已获得批准，该产品就是利用IPS细胞分化而来的心肌细胞制成的。它可以通过静脉注射方式用于治疗严重慢性缺血性心力衰竭。与传统的治疗方法相比，这种治疗方法不仅更加安全，还能够显著改善患者的心功能和生命质量。化学诱导法的发展进一步丰富了体细胞“重编程”的方法。通过使用一些化学小分子，可以促使体细胞重新变成具有多能性的干细胞，进而分化成心肌细胞。这种方法的优点在于操作简便、效率高，而且可以避免使用基因编辑技术进行细胞改造所可能带来的伦理问题。此外，利用患者自身细胞加工形成的iPS细胞，其培养出的组织或器官在重新移植到患者体内后将被认定为自体组织，因此能够避开免疫***的攻击。这种方法的优点在于避免了免疫排斥反应，从而提高了治疗的安全性和有效性。
总之，IPS细胞分化为心肌细胞的技术在心力衰竭治疗领域展现出了广阔的应用前景。在未来，随着相关研究的深入，这项技术有望为更多患者带来福音。但是目前，针对IPS细胞分化为心肌细胞的研究还不够多，提供可选择的替代产品还不够成熟。
发明内容
本发明针对现有技术的不足，提供了一种诱导性心肌细胞联合丹参注射液用于治疗心力衰竭的方法。
具体的所述的心肌细胞为申请人在先专利申请（申请号：CN202311628005.4）中明确记载的方法制备获得的。
具体的，所述的心肌细胞的制备方法为：将皮肤成纤维细胞调整细胞数为1×106个，100μl电转缓冲液中加入 3μl Epi5TM Episomal iPSC 重编程试剂盒中的重编程因子，采用常规电转染细胞按2ml/孔接种于基质胶包被的6孔板中，置于培养箱中培养；并使用ReproTeSRTM重编程培养基隔天换液，转染后第8天，将细胞消化后重新接种在第5代小鼠成纤维细胞制作的饲养层上，培养18天，观察iPSCs可见典型的克隆，将ips克隆重新接种于基质胶包被的6孔板中，置于培养箱中培养，使用mTeSRTM培养基继续培养；根据CardioEasy®人心肌细胞分化试剂盒说明配制心肌分化完全培养基I、II、Ⅲ液，将制备的iPSCs细胞生长至80%融合时吸去原液，PBS清洗，加入2mL心肌分化Ⅰ液其中含有SKP2-3F2单克隆抗体终浓度200μg/mL，48h后吸去旧液，PBS清洗后加入心肌分化Ⅱ液其中含有权利要求1中所述的SKP2-3F2单克隆抗体终浓度为200μg/mL；48h后更换为心肌分化Ⅲ液其中含有SKP2-3F2单克隆抗体终浓度200μg/mL，37℃、5%CO2培养箱持续培养，每48h更换培养液，每次更换的培养液中均含有SKP2-3F2单克隆抗体终浓度200μg/mL，直至观察到细胞搏动，即得分化的心肌细胞。所述的SKP2单克隆抗体其轻链可变区序列如SEQ ID NO：1所示，重链可变区序列如SEQ ID NO：2所示。该单抗的亲和力为5.63×109M-1，能够特异性的识别并抑制SKP2蛋白的功能。该单抗是以SKP2重组蛋白免疫小鼠后通过杂交瘤技术制备获得的单克隆抗体，具体参见申请人在先专利申请（申请号：CN202311628005.4）中明确记载。
进一步的，本发明提供一种用于治疗心力衰竭的药物组合，所述的药物组合是由本发明诱导分化的心肌细胞以及丹参注射液组成。
具体的，本发明的心肌细胞的移植量约为1×106～5×106个。
丹参注射液的剂量为1-10g/（kg· d）。
进一步的，本发明的药物组合中的心肌细胞含有药学上可接受的载体组成。
适合的药学上可接受的赋形剂的实例包括一种或多种聚合物、润湿剂或表面活性剂、pH调节剂、等渗调节剂、防腐剂、缓冲剂以及螯合剂、或它们的任意组合。
适合的药学上可接受的pH调节剂的实例包括但不限于氢氧化钠、柠檬酸、盐酸、硼酸、乙酸、磷酸、琥珀酸、氢氧化钠、氢氧化钾、氢氧化铵、氧化镁、碳酸钙、碳酸镁、硅酸铝镁、苹果酸、柠檬酸钾、柠檬酸钠、磷酸钠、乳酸、葡糖酸、酒石酸、1,2,3,4-丁烷四羧酸、富马酸、二乙醇胺、单乙醇胺、碳酸钠、碳酸氢钠、三乙醇胺或它们的任意组合。在一个实施方案中，所述药学上可接受的pH调节剂的存在量为约0.01％至约2.0％(重量/体积)，优选约0.05％至约1％(重量/体积)。
适合的药学上可接受的防腐剂的实例包括但不限于苯扎氯铵、苄索氯铵和氯化十六烷基吡啶、溴化苄、苄醇、EDTA二钠、硝酸苯汞、乙酸苯汞、乙基汞硫代水杨酸钠、硫柳汞、乙酸盐和硼酸苯汞、硫酸多粘菌素B、氯己定、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、苯乙醇、氯化季铵盐、苯甲酸钠、丙酸钠、稳定的氯氧复合物(stabilized oxychloro complex)、山梨酸或它们的混合物。优选的药学上可接受的防腐剂包括EDTA二钠(乙二胺四乙酸二钠)和苯扎氯铵或它们的混合物。在一个实施方案中，所述药学上可接受的防腐剂的存在量为约0.01％至约2.0％(重量/体积)，优选约0.05％至约1％(重量/体积)。
适合的药学上可接受的缓冲剂的实例包括但不限于氯化钠、葡萄糖、乳糖和磷酸盐缓冲盐水(PBS)或者它们的任意组合。其他适合的药学上可接受的缓冲剂包括但不限于琥珀酸二钠六水合物、硼酸盐、柠檬酸盐、磷酸盐、乙酸盐、生理盐水、tris-HCl(三(羟甲基)氨基甲烷盐酸盐)、HEPES(N-2-羟乙基哌嗪-N'-2-乙磺酸(N-2-hydroxyethyl piperazine-N1-2-ethane sulfonic acid))、磷酸钠、硼酸钠、生理盐水、柠檬酸盐、碳酸盐、磷酸盐和/或它们的混合物，以获得期望的同渗容摩(osmolarity)。在一个实施方案中，所述药学上可接受的缓冲剂的存在量为约0.01％至约2.0％(重量/体积)，优选约0.05％至约1％(重量/体积)。
适合的药学上可接受的螯合剂的实例包括但不限于乙二胺四乙酸(EDTA)、EDTA二钠及其衍生物、柠檬酸及其衍生物、烟酰胺及其衍生物、脱氧胆酸钠及其衍生物、或这些螯合剂的混合物。在一个实施方案中，所述药学上可接受的螯合剂的存在量为约0.01％至约2.0％(重量/体积)，优选约0.05％至约1％(重量/体积)。
适合的药学上可接受的聚合物的实例包括但不限于纤维素衍生物(例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、甲基纤维素聚合物、羟乙基纤维素、羧甲基纤维素钠、羧亚甲基羟乙基纤维素和羧甲基羟乙基纤维素(carboxymethylene andcarboxymethyl hydroxyethylcellulose)或它们的任意组合)、丙烯酸酯类(例如丙烯酸、丙烯酰胺和马来酸酐聚合物、共聚物或它们的混合物)，以及它们的混合物。也可以使用聚合物共混物。优选的药学上可接受的聚合物为羟乙基纤维素。在一个实施方案中，所述药学上可接受的聚合物的存在量为约0.01％至约5.0％(重量/体积)，优选约0.05％至约2％(重量/体积)，更优选约0.1％至约1.0％(重量/体积)，例如约0.1％、0.2％、0.5％或1.0％(重量/体积)。
适合的药学上可接受的润湿剂或表面活性剂的实例包括但不限于两性、非离子型、阳离子型或阴离子型分子。适合的表面活性剂包括但不限于聚山梨酯、十二烷基硫酸钠(月桂基硫酸钠)、十二烷基二甲基氧化胺、多库酯钠、十六烷基三甲基溴化铵(CTAB)、聚乙氧基化醇、聚氧乙烯脱水山梨醇、辛苯昔醇、N,N-二甲基十二烷基胺-N-氧化物、十六烷基三甲基溴化铵、聚氧乙烯(10)月桂醚、 表面活性剂(由月桂醇、鲸蜡醇、硬脂醇和油醇衍生的植物油系脂肪醇聚氧乙烯醚)、胆盐(例如脱氧胆酸钠和胆酸钠)、聚氧乙烯蓖麻油、壬基酚乙氧基化物、环糊精、卵磷脂、甲苄索氯铵、羧酸盐、磺酸盐、石油磺酸盐、烷基苯磺酸盐、萘磺酸盐、烯烃磺酸盐、烷基硫酸盐、硫酸盐、硫酸化天然油和脂肪、硫酸化酯、硫酸化烷醇酰胺、烷基酚(乙氧基化和硫酸化的)、乙氧基化脂肪醇、聚氧乙烯表面活性剂、羧酸酯、聚乙二醇酯、脱水山梨醇酯及其乙氧基化衍生物、脂肪酸乙二醇酯、羧酰胺、单烷醇胺缩合物、聚氧乙烯脂肪酸酰胺、季铵盐、具有酰胺键的胺、聚氧乙烯烷基胺和聚氧乙烯脂环族胺、N,N,N,N-四取代乙二胺、2-烷基-1-羟乙基-2-咪唑啉、N-椰油基-3-氨基丙酸/钠盐(N-coco 3-aminopropionic acid/sodium salt)、N-牛脂基-3-亚氨基二丙酸二钠盐(N-tallow 3-iminodipropionate disodium salt)、N-羧甲基-N,N-二甲基-N-9-十八烯基氢氧化铵(N-carboxymethyl n dimethyl n-9octadecenyl ammonium hydroxide)、N-椰油酰胺乙基-N-羟乙基甘氨酸钠盐等、聚氧乙烯、脱水山梨醇单月桂酸酯和硬脂酸酯、 (聚乙氧基化蓖麻油)、 (环氧乙烷/12-羟基硬脂酸)、聚山梨酯、四丁酚醛，以及它们的任意组合。优选的药学上可接受的表面活性剂包括四丁酚醛和(脱水山梨醇单油酸酯)或其混合物。
本发明进一步的提供一种治疗心脏疾病的方法，包括给予本发明诱导的心肌细胞。在一些实施方案中，心脏病况或疾病选自小儿心肌病、年龄相关性心肌病、扩张型心肌病、肥厚型心肌病、限制性心肌病、慢性缺血性心肌病、围产期心肌病、炎症性心肌病、其他心肌病、心肌炎、心肌缺血再灌注损伤、心室功能障碍、心力衰竭、充血性心力衰竭、冠状动脉疾病、终末期心脏病、动脉粥样硬化、局部缺血、高血压、再狭窄、心绞痛、风湿性心脏病、动脉炎症或心血管疾病。
该方法包括施用包含治疗有效量的本文所述的任一种分离的、工程化的分化的心肌细胞的组合物。在一些实施方案中，该组合物还包含治疗有效的载体。在一些实施方案中，施用包括植入患者的心脏组织、静脉内注射、动脉内注射、冠状动脉内注射、肌内注射、腹膜内注射、心肌内注射、经心内膜注射、经心外膜注射或输注。
在一些实施方案中，血管病况或疾病选自血管损伤、心血管疾病、血管疾病、缺血性疾病、心肌梗塞、充血性心力衰竭、高血压、缺血性组织损伤、肢体缺血、中风、神经病和脑血管疾病。
在一些实施方案中，还向施用分化心脏细胞的患者施用了心脏药物。适用于联合疗法的心脏药物的举例说明性示例包括但不限于生长因子、编码生长因子的多核苷酸、血管生成剂、钙通道阻滞剂、降压剂、抗有丝***剂、正性肌力药、抗动脉粥样硬化剂、抗凝剂、β受体阻滞剂、抗心律失常药、抗炎药、血管扩张药、溶栓药、强心苷、抗生素、抗病毒药、抗真菌药、抑制原生动物的药物、硝酸盐、血管紧张素转换酶(ACE)抑制剂、血管紧张素II受体拮抗剂、脑钠肽(BNP)；抗肿瘤药、类固醇等。
有益效果
本发明提供了一种单用单抗处理提高ips细胞诱导分化为心肌细胞的方法。进一步的将所述的诱导分化获得的心肌细胞与丹参注射液一起使用后具有较好的治疗心肌梗死的效果，将二者组合使用后可以有效地用于制备心力衰竭的药物组合，应用前景较好。
附图说明
图1 细胞注射后各组超声心动图LVFS检查结果比较
图2 细胞注射后各组超声心动图LVEF检查结果比较
实施方式
下面将参照附图更详细地描述本发明的具体实施例。虽然附图中显示了本发明的具体实施例，然而应当理解，可以以各种形式实现本发明而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本发明，并且能够将本发明的范围完整的传达给本领域的技术人员。
尽管本文使用了特定的术语，但它们仅用于一般性和描述性的意义，而不是为了限制的目的。除非另有定义，否则本文使用的所有技术和科学术语具有与本公开描述的主题所属领域的普通技术人员通常理解的相同的含义。
实施例1 皮肤成纤维细胞制备ips细胞
取手术后分离的儿童***皮肤约0.3cm×0.3cm， 将其置于含有青霉素(100kU/L)和链霉素(100mg/L)的HBSS中反复漂洗后，去除皮下脂肪。在60mm培养皿中用眼科剪将皮肤剪成1mm2大小，置于含有青霉素(100kU/L)和链霉素(100mg/L)的DMEM/F12(1:1)液3ml 37℃下置于体积分数为5%的CO2、95%空气、饱和湿度孵箱中过夜。次日挑除汗腺腺体，待成纤维细胞生长明显时，吸弃旧培养液，用无Na+、Mg2+的HBSS洗2次，加入含有质量分数为0.25%胰酶和0.02%乙二胺四乙酸(EDTA)的D-Hank消化液约1ml 37℃下置于5%CO2、95%空气、饱和湿度条件下孵育2min，加入含10%胎牛血清的DMEM约2ml终止消化，1000r/min离心6min并收集细胞，用含胎牛血清(10%)、青霉素(100kU/L)和链霉素(100mg/L)的DMEM 分散细胞，细胞以1x104/ml接种4ml至25cm²的培养瓶中，在37℃、5%CO2、95%空气、饱和湿度条件下培养，经过连续5次传代培养后，可得到纯化的成纤维细胞。去少量细胞进行HE染色发现，细胞为长梭形，细胞核为淡蓝色，细胞浆为粉红色，通过染色体核型分析显示为46条染色体，鉴定制备获得了较为纯净的成纤维细胞。
将分离培养的皮肤成纤维细胞调整细胞数为1×106个，100μl电转缓冲液中加入3μl Epi5TM Episomal iPSC 重编程试剂盒中的重编程因子，采用常规电转染细胞按2ml/孔接种于基质胶包被的6孔板中，置于培养箱中培养。并使用ReproTeSRTM重编程培养基隔天换液，转染后第8天，将细胞消化后重新接种在5代小鼠成纤维细胞制作的饲养层上，第18天，观察iPSCs可见典型的克隆，采用试剂盒检测干细胞多能性基因发现OCT4、SOX2、NANOG、KLF4和LIN28均阳性表达，表明制备获得了ips细胞。将筛选的阳性ips克隆重新接种于基质胶包被的6孔板中，置于培养箱中培养，使用mTeSRTM培养基继续培养，筛选纯化后备用。
进一步的，为了检验ips细胞的活性，将制备的ips细胞体外悬浮培养形成EB，裂解细胞提取RNA，用于RT-PCR检测EB细胞基因表达量，结果显示，EB细胞的胚层分化基因外胚层Nestin、中胚层Eomes、内胚层AFP的表达水平均显著高于对照组ips细胞5倍以上（P<0.01），实验结果表明所建立的人ips细胞具有体外分化能力。
实施例2 ips细胞向心肌细胞的分化
无抗体诱导组：根据CardioEasy®人心肌细胞分化试剂盒(北京赛贝生物技术有限公司,货号CA2004500)说明配制心肌分化完全培养基I、II、Ⅲ液，平衡至室温。实施例4制备的iPSCs细胞生长至80%融合时吸去原液，PBS清洗，加入2mL心肌分化Ⅰ液，48h后吸去旧液，PBS清洗后加入心肌分化Ⅱ液；48h后更换为心肌分化Ⅲ液，37℃、5%CO2培养箱持续培养，每48h更换培养液，直至观察到细胞搏动。
有抗体诱导组：实施例1制备的iPSCs细胞生长至80%融合时吸去原液，PBS清洗，加入2mL心肌分化Ⅰ液（其中含有SKP2-3F2单克隆抗体终浓度为200μg/mL），48h后吸去旧液，PBS清洗后加入心肌分化Ⅱ液（其中含有SKP2-3F2单克隆抗体终浓度为200μg/mL）；48h后更换为心肌分化Ⅲ液（其中SKP2-3F2单克隆抗体终浓度200μg/mL），37℃、5%CO2培养箱持续培养，每48h更换培养液，每次更换的培养液中均含有终浓度为实施例2纯化的SKP2-3F2单克隆抗体200μg/mL，直至观察到细胞搏动。
2组继续诱导到15d，收集搏动细胞1×107个/mL备用。搏动细胞采用4%多聚甲醛固定，0.2%TritonX-100处理1h，5%脱脂牛奶孵育2h，TNNT-2（1∶200）和α-actinin一抗孵育，加入AlexaFluor488二抗常温孵育，胞核DAPI染色，荧光显微镜观察拍照。结果显示搏动细胞中均表达心肌标志物TNNT-2和α-actinin，说明分化成为了有活性的心肌细胞。
实施例3 心肌梗死小鼠模型的构建及治疗效果验证
取BALB/C雄性小鼠按照随机数字表法分为正常组（不干预）、急性心肌梗死组（AMI造模）、实验组1（急性心肌梗死造模+无抗体诱导心肌细胞注射）、实验组2（急性心肌梗死造模+无抗体诱导心肌细胞注射+丹参注射液灌胃）、实验组3（急性心肌梗死造模+抗体诱导心肌细胞注射）、实验组4（急性心肌梗死造模+抗体诱导心肌细胞注射+丹参注射液灌胃），每组5只。
心肌梗死小鼠模型建模方法是小鼠局麻后颈部正中切口，22G针穿入气管，连接人工呼吸机，左胸4-5肋间进入胸腔，分离心包膜，于主动脉根部4-5mm、肺动脉与左心耳间8-0缝线穿过冠状动脉左前降支结扎，远端呈现暗红色提示成功，逐层缝合胸腔，多导生理记录仪行心电图即刻描记,超声心动图检查呈现典型的左心室重构特征，表现为左心室心腔扩大（LVDd和LVDs增加），左心室收缩能力减弱（LVEF和LVFS减小），提示AMI动物模型制备成功。
PBS重悬前述制备的诱导心肌细胞，调整密度为2×107/mL，术后30min将20μL悬液注射到梗死心肌区域周围，关闭胸腔、逐层缝合。恢复自主呼吸后拔出插管，严密缝合，肌内注射20000U青霉素，单笼饲养；丹参注射液剂量为［5g/（kg·d）］［相当于成人剂量0.560g/（kg·d）］，灌胃给药。
心功能评估术后第15天行超声心动图检查，记录左心室舒张末期内径（LVDd）、左心室收缩末期内径（LVDs）、左心室舒张末期容积（LEDV）、左心室收缩末期容积（LESV），计算左心室射血分数（LVEF）和左心室短轴缩短率（LVFS）。LVEF=（EDV-ESV）/EDV；LVFS=（LVDd-LVDs）/LVDd×100%。统计学方法采用GraphPadPrism8.02软件进行数据分析。符合正态分布的计量资料以均数±标准差（x±s）表示，多组间均数比较采用单因素方差分析，组间多重比较采用GamesHowell检验。P＜0.05为差异有统计学意义。结果如图1和图2所示。
从图1可以看出，模型组相较于正常组，其LVFS显著下降，P<0.01。实验组1-4经过治疗后，LVFS均得到显著的提高，从图1可以看出，采用抗体诱导的心肌细胞治疗的LVFS值（实验组3）要比未采用抗体诱导的心肌细胞治疗的LVFS值（实验组1）要高约10%的效果，这从侧面说明，采用单抗诱导的心肌细胞具有更好的生物学活性。采用丹参注射液灌协同治疗后，能够有效的提高LVFS的值，这也说明丹参注射液能够通过本领域已知的激活Akt通路来抑制心肌细胞凋亡，促进细胞增殖来提高心肌梗死的治疗效果。
从图2结果可以看出，与图1结果类似模型组相较于正常组，其LVEF显著下降，P<0.01。实验组1-4经过治疗后，LVEF均得到显著的提高，从图2可以看出，采用抗体诱导的心肌细胞治疗的LVEF值（实验组3）要比未采用抗体诱导的心肌细胞治疗的LVEF值（实验组1）要高约3.4%的效果，这从侧面说明，采用单抗诱导的心肌细胞具有更好的生物学活性。采用丹参注射液灌协同治疗后，能够有效的提高LVEF的值。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，但本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (3)
1.一种用于治疗心力衰竭的药物组合物，其特征在于由IPS诱导定向分化成的心肌细胞和丹参注射液组成；其中IPS诱导定向分化成的心肌细胞是采用如下方法制备获得：将皮肤成纤维细胞调整细胞数为1×106个，100μl电转缓冲液中加入 3μl Epi5TM EpisomaliPSC 重编程试剂盒中的重编程因子，采用常规电转染细胞按2ml/孔接种于基质胶包被的6孔板中，置于培养箱中培养；并使用ReproTeSRTM重编程培养基隔天换液，转染后第8天，将细胞消化后重新接种在第5代小鼠成纤维细胞制作的饲养层上，培养18天，观察iPSCs可见典型的克隆，将ips克隆重新接种于基质胶包被的6孔板中，置于培养箱中培养，使用mTeSRTM培养基继续培养；根据CardioEasy®人心肌细胞分化试剂盒说明配制心肌分化完全培养基I、II、Ⅲ液，将制备的iPSCs细胞生长至80%融合时吸去原液，PBS清洗，加入2mL心肌分化完全培养基Ⅰ液，其中含有SKP2-3F2单克隆抗体终浓度200μg/mL，48h后吸去旧液，PBS清洗后加入心肌分化完全培养基Ⅱ液，其中含有SKP2-3F2单克隆抗体终浓度为200μg/mL；48h后更换为心肌分化完全培养基Ⅲ液，其中含有SKP2-3F2单克隆抗体终浓度200μg/mL，37℃、5%CO2培养箱持续培养，每48h更换培养液，每次更换的培养液中均含有SKP2-3F2单克隆抗体终浓度200μg/mL，直至观察到细胞搏动，即得分化的心肌细胞，所述的SKP2-3F2单克隆抗体其轻链可变区序列如SEQ ID NO：1所示，重链可变区序列如SEQ ID NO：2所示。
2.IPS诱导定向分化成的心肌细胞和丹参注射液在制备用于治疗心力衰竭的药物组合物中的用途，其中所述的IPS诱导定向分化成的心肌细胞采用权利要求1中所述的方法制备获得。
3.如权利要求2所述的用途，其中所述的IPS诱导定向分化成的心肌细胞的移植量为1×106～5×106个。
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