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Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives.

ABSTRACT: In the ongoing quest for the "ideal" cell type for heart repair, pluripotent stem cells (PSC) derived from either embryonic or reprogrammed somatic cells have emerged as attractive candidates because of their unique ability to give rise to lineage-specific cells and to transplant them at the desired stage of differentiation. The technical obstacles which have initially hindered their clinical use have now been largely overcome and several trials are under way which encompass several different diseases, including heart failure. So far, there have been no safety warning but it is still too early to draw definite conclusions regarding efficacy. In parallel, mechanistic studies suggest that the primary objective of "remuscularizing" the heart with PSC-derived cardiac cells can be challenged by their alternate use as ex vivo sources of a biologically active extracellular vesicle-enriched secretome equally able to improve heart function through harnessing endogenous repair pathways. The exclusive use of this secretome would combine the advantages of a large-scale production more akin to that of a biological medication, the likely avoidance of cell-associated immune and tumorigenicity risks and the possibility of intravenous infusions compatible with repeated dosing.

SUBMITTER: Menasche P

PROVIDER: S-EPMC7649799 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives.

Menasché Philippe P

Frontiers in bioengineering and biotechnology 20201026

In the ongoing quest for the "ideal" cell type for heart repair, pluripotent stem cells (PSC) derived from either embryonic or reprogrammed somatic cells have emerged as attractive candidates because of their unique ability to give rise to lineage-specific cells and to transplant them at the desired stage of differentiation. The technical obstacles which have initially hindered their clinical use have now been largely overcome and several trials are under way which encompass several different di ...[more]

PMID: 33195177

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Project description:RationaleMyofibroblasts 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.ObjectiveTo 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 resultsWhen 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 <7% of transplanted cells ( P<0.01, each cell type) in animals that were treated with both hiPSC-NMCCs and the TGF-β inhibitor galunisertib. Galunisertib coadministration was also associated with significant improvements in fibrotic area, left ventricular dilatation, vascular density, and cardiac function.ConclusionshiPSC-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.

Dataset Information

Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives.

Publications

Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives.

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