Key result
CPC-derived iPSCs boost differentiation efficiency over fibroblast lines but yield comparable post-MI functional recovery.
While epigenetic memory improves the in vitro differentiation efficiency of iPSC-CMs derived from cardiac versus non-cardiac sources, it does not lead to improved functional outcomes in vivo.
Background Human-induced pluripotent stem cells (iPSCs) are a potentially unlimited source for generation of cardiomyocytes (iPSC-CMs). However, current protocols for iPSC-CM derivation face a number of challenges, including variability in somatic cell sources and inconsistencies in cardiac differentiation efficiency. Objectives We aimed to assess the effect of epigenetic memory on differentiation and function of iPSC-CMs generated from somatic cell sources of cardiac versus non-cardiac origins. Methods Cardiac progenitor cells (CPCs) and skin fibroblasts from the same donors were reprogrammed into iPSCs and differentiated into iPSC-CMs via embryoid body and monolayer-based differentiation protocols. Results Differentiation efficiency was found to be higher in CPC-derived iPSC-CMs (CPC-iPSC-CMs) than in fibroblast-derived iPSC-CMs (Fib-iPSC-CMs). Gene expression analysis during cardiac differentiation demonstrated upregulation of cardiac transcription factors in CPC-iPSC-CMs, including NKX2-5, MESP1, ISL1, HAND2, MYOCD, MEF2C, and GATA4. Epigenetic assessment revealed higher methylation in the promoter region of NKX2-5 in Fib-iPSC-CMs compared to CPC-iPSC-CMs. Epigenetic differences were found to dissipate with increased cell passaging, and a battery of in vitro assays revealed no significant differences in their morphological and electrophysiological properties at early passage. Finally, cell delivery into small animal myocardial infarction (MI) model indicated that CPC-iPSC-CMs and Fib-iPSC-CMs possess comparable therapeutic capabilities in improving functional recovery in vivo. Conclusions This is the first study to compare differentiation of iPSC-CMs from human CPCs versus human fibroblasts from the same donors. We demonstrate that while epigenetic memory improves differentiation efficiency of cardiac versus non-cardiac somatic cell source in vitro, it does not contribute to improved functional outcome in vivo.
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Sánchez-Freire et al. (2014) studied Myocardial Infarction (animal model). Cardiac progenitor cells (CPCs) as somatic cell source vs. Skin fibroblasts from the same donors was evaluated on Differentiation efficiency and in vivo functional recovery. Cardiac progenitor cell-derived iPSCs showed higher differentiation efficiency in vitro than fibroblast-derived iPSCs, but both provided comparable functional recovery in a myocardial infarction model.
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