Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells
| Autor: | Zhaohui Geng, Glenn R. Gourley, Ling Gao, Yuhua Wei, Lu Wang, Jianyi Zhang, Libang Yang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Swine Physiology Induced Pluripotent Stem Cells Myocardial Infarction Smad Proteins Mice SCID 030204 cardiovascular system & hematology Article Cardiac cell Cell Line Mice 03 medical and health sciences 0302 clinical medicine Smooth muscle Mice Inbred NOD Transforming Growth Factor beta Precursor cell medicine Animals Humans Cellular Reprogramming Techniques Myocardial infarction Myofibroblasts Cells Cultured Chemistry TOR Serine-Threonine Kinases medicine.disease 030104 developmental biology Cell Transdifferentiation Quinolines Cancer research Pyrazoles Female Snail Family Transcription Factors Cardiology and Cardiovascular Medicine Myofibroblast Stem Cell Transplantation |
| Zdroj: | Circulation Research. 123:1313-1325 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.118.313094 |
| Popis: | 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-β (transforming growth factor-β), the expression of myofibroblast markers increased, whereas endothelial cell, smooth muscle cell, pericyte, and fibroblast marker expression declined. TGF-β–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 cell-derived, pericyte-derived, and fibroblast-derived myofibroblast-like cells differed. Furthermore, when hiPSC-NMCCs were transplanted into the hearts of mice after myocardial infarction, ≈21% to 35% of the transplanted hiPSC-NMCCs expressed myofibroblast markers 1 week later, compared with P Conclusions: hiPSC-NMCCs differentiate into myofibroblast-like cells when cultured with TGF-β or when transplanted into infarcted mouse hearts, and the phenotypes of the myofibroblast-like cells can differ depending on the lineage of origin. TGF-β inhibition significantly improved the efficacy of transplanted hiPSC-NMCCs for cardiac repair, perhaps by limiting the differentiation of hiPSC-NMCCs into myofibroblast-like cells. |
| Databáze: | OpenAIRE |
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