基于诱导多能干细胞治疗急性心肌梗死的临床前研究进展

Progress in preclinical research on induced pluripotent stem cell therapy for acute myocardial infarction

诱导多能干细胞(iPSC)是通过导入外源基因或在培养基中加入化学物质等方法使体细胞去分化而获得。与胚胎干细胞类似,iPSC可以分化形成三种胚层细胞系。iPSC能通过二维分化方法(如单层细胞培养和共培养),或拟胚体诱导法和基于支架的三维细胞培养方法分化为心肌细胞。iPSC分化成心肌细胞的过程还需通过激活或抑制特定的信号通路(如Wnt、BMP、Notch信号通路)来模拟体内心脏发育过程。近年来,通过生物反应器进行细胞悬浮培养,已能产生足够数量的iPSC衍生的心肌细胞(iPSC-CM)。iPSC-CM在移植前需要通过代谢调节和细胞分选等方法进行纯化,以消除可能导致畸胎瘤形成的未分化iPSC。目前,iPSC-CM的主要移植方法为细胞悬液注射和细胞片移植。动物实验研究表明,将iPSC-CM移植到梗死心肌中能改善心脏功能。本文综述了上述关于iPSC-CM治疗急性心肌梗死的临床前相关研究,并讨论了iPSC-CM在临床应用中的局限性和挑战,以期为iPSC-CM的临床转化研究提供参考。

Induced pluripotent stem cells(iPSCs)are obtained by introducing exogenous genes or adding chemicals to the culture medium to induce somatic cell differentiation.Similarly to embryonic stem cells,iPSCs have the ability to differentiate into all three embryonic cell lines.iPSCs can differentiate into cardiac muscle cells through two-dimensional differentiation methods such as monolayer cell culture and co�culture,or through embryoid body and scaffold-based three-dimensional differentiation methods.In addition,the process of iPSCs differentiation into cardiac muscle cells also requires activation or inhibition of specific signaling pathways,such as Wnt,BMP,Notch signaling pathways to mimic the development of the heart in vivo.In recent years,suspension culturing in bioreactors has been shown to produce large number of iPSCs derived cardiac muscle cells(iPSC-CMs).Before transplantation,it is necessary to purify iPSC-CMs through metabolic regulation or cell sorting to eliminate undifferentiated iPSCs,which may lead to teratoma formation.The transplantation methods for iPSC-CMs are mainly injection of cell suspension and transplantation of cell patches into the infarcted myocardium.Animal studies have shown that transplantation of iPSC-CMs into the infarcted myocardium can improve cardiac function.This article reviews the progress in preclinical studies on iPSC-CMs therapy for acute myocardial infarction and discusses the limitations and challenges of its clinical application to provide references for further clinical research and application.