Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells
Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells
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DOI：
10.1161/circresaha.118.313094
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发表时间：
2018-12-07
影响因子：
20.1
通讯作者：
Zhang, Jianyi
中科院分区：
文献类型：
--
作者：
Gao, Ling;Yang, Libang;Zhang, Jianyi
原理：肌成纤维细胞被认为是由前体细胞进化而来；然而，从人诱导的多能干细胞（hiPSCs）中提取的非心肌细胞心肌细胞（NMCCs，即内皮细胞、平滑肌细胞、周细胞和成纤维细胞）是否可以转分化为肌成纤维细胞样细胞，如果可以，这一过程是否会降低hiPSC-NMCC治疗的疗效，目前尚不清楚。目的：探讨hipsc - nmcc能否向肌成纤维样细胞分化，以及限制其转分化是否能提高其心肌修复效果。方法和结果：用tgf - β（转化生长因子- β）培养由hiPSCs生成的内皮细胞、平滑肌细胞、周细胞和成纤维细胞时，肌成纤维细胞标志物的表达增加，而内皮细胞、平滑肌细胞、周细胞和成纤维细胞标志物的表达下降。tgf - β相关的肌成纤维细胞分化伴随着Smad、Snail和mTOR（哺乳动物雷帕霉素靶点）信号活性的增加。然而，hipsc来源的内皮细胞、平滑肌细胞、周细胞来源和成纤维细胞来源的肌成纤维细胞样细胞的通路激活、增殖、凋亡、迁移和蛋白质表达的测量结果不同。此外，当心肌梗死后将hiPSCNMCCs移植到小鼠心脏时，大约21%至35%的移植hiPSCNMCCs在1周后表达肌成纤维细胞标志物，而同时使用hiPSCNMCCs和tgf - β抑制剂galunisertib处理的动物移植细胞中，这一比例为< 7% （P< 0.01，每种细胞类型）。Galunisertib与纤维化面积、左心室扩张、血管密度和心功能的显著改善也相关。结论：hipsc - nmcc在tgf - β培养或移植到梗死小鼠心脏时可分化为肌成纤维细胞样细胞，并且肌成纤维细胞样细胞的表型可因起源谱系而异。tgf - β抑制可能通过限制hipsc - nmcs向肌成纤维样细胞的分化，显著提高了移植的hipsc - nmcs的心脏修复效果。
Rationale: Myofibroblasts are believed to evolve from precursor cells; however, whether noncardiomyocyte cardiac cells (NMCCs; ie, endothelial cells, smooth muscle cells, pericytes, and fibroblasts) that have been derived from human-induced pluripotent stem cells (hiPSCs) can transdifferentiate into myofibroblast-like cells, and if so, whether this process reduces the efficacy of hiPSC-NMCC therapy, is unknown.Objective: To determine whether hiPSC-NMCCs can differentiate to myofibroblast-like cells and whether limiting the transdifferentiation of hiPSC-NMCCs can improve their effectiveness for myocardial repair.Methods and Results: When endothelial cells, smooth muscle cells, pericytes, and fibroblasts that had been generated from hiPSCs were cultured with TGF-beta (transforming growth factor-beta), the expression of myofibroblast markers increased, whereas endothelial cell, smooth muscle cell, pericyte, and fibroblast marker expression declined. TGF-beta-associated myofibroblast differentiation was accompanied by increases in the signaling activity of Smad, Snail, and mTOR (mammalian target of rapamycin). However, measures of pathway activation, proliferation, apoptosis, migration, and protein expression in hiPSC-endothelial cell-derived, smooth muscle cellderived, pericyte-derived, and fibroblast-derived myofibroblast-like cells differed. Furthermore, when hiPSCNMCCs were transplanted into the hearts of mice after myocardial infarction, approximate to 21% to 35% of the transplanted hiPSC-NMCCs expressed myofibroblast markers 1 week later, compared with < 7% of transplanted cells (P< 0.01, each cell type) in animals that were treated with both hiPSC-NMCCs and the TGF-beta inhibitor galunisertib. Galunisertib coadministration was also associated with significant improvements in fibrotic area, left ventricular dilatation, vascular density, and cardiac function.Conclusions: hiPSC-NMCCs differentiate into myofibroblast-like cells when cultured with TGF-beta or when transplanted into infarcted mouse hearts, and the phenotypes of the myofibroblast-like cells can differ depending on the lineage of origin. TGF-beta inhibition significantly improved the efficacy of transplanted hiPSC-NMCCs for cardiac repair, perhaps by limiting the differentiation of hiPSC-NMCCs into myofibroblast-like cells.