iPS Programmed Without c-MYC Yield Proficient Cardiogenesis for Functional Heart Chimerism

摘要: Rationale: Induced pluripotent stem cells (iPS) allow derivation of progenitors from somatic sources. Originally, iPS were induced by a stemness-related gene set that included the c-MYC oncogene. Objective: Here, we determined embryo to adult cardiogenic proficiency programmed without c-MYC, cardiogenicity-associated transcription factor. Methods and Results: Transgenic expression 3 human stemness factors SOX2, OCT4, KLF4 here reset murine fibroblasts ground state. Transduction reversed cellular ultrastructure into primitive archetype cell markers generating 3-germ layers, all qualifiers acquired pluripotency. Three-factor (3F-iPS) clones reproducibly demonstrated cardiac differentiation properties characterized vigorous beating activity embryoid bodies robust Mef2c, α-actinin, connexin43, MLC2a, troponin I. In vitro isolated iPS-derived cardiomyocytes functional excitation-contraction coupling. Chimerism with 3F-iPS derived morula-stage diploid aggregation was sustained during prenatal heart organogenesis contributed in vivo normal structure overall performance tumor-free offspring. Conclusions: Thus, bioengineered achieve highest stringency criteria for bona fide cardiogenesis enabling reprogrammed yield de novo tissue compatible native counterpart throughout embryological development adulthood.