Reprogramming of skeletal myoblasts for induction of pluripotency for tumor-free cardiomyogenesis in the infarcted heart

Rafeeq P.H. Ahmed, Husnain K. Haider, Stephanie Buccini, Longhu Li, Shujia Jiang, Muhammad Ashraf

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Rationale: Skeletal myoblasts (SMs) with inherent myogenic properties are better candidates for reprogramming to pluripotency. Objective: To reprogram SMs to pluripotency and show that reprogrammed SMs (SiPS) express embryonic gene and microRNA profiles and that transplantation of predifferentiated cardiac progenitors reduce tumor formation. Methods and Results: The pMXs vector containing mouse cDNAs for Yamanaka's quartet of stemness factors were used for transduction of SMs purified from male Oct4-GFP transgenic mouse. Three weeks later, GFP colonies of SiPS were isolated and propagated in vitro. SiPS were positive for alkaline phosphatase, expressed SSEA1, and displayed a panel of embryonic stem (ES) cell-specific pluripotency markers. Embryoid body formation yielded beating cardiomyocyte-like cells, which expressed early and late cardiac-specific markers. SiPS also had an microRNA profile that was altered during their cardiomyogenic differentiation. Noticeable abrogation of let-7 family and significant up-regulation of miR-200a-c was observed in SiPS and SiPS-derived cardiomyocytes, respectively. In vivo studies in an experimental model of acute myocardial infarction showed extensive survival of SiPS and SiPS-derived cardiomyocytes in mouse heart after transplantation. Our results from 4-week studies in DMEM without cells (group 1), SMs (group-2), SiPS (group-3), and SiPS-derived cardiomyocytes (group 4) showed extensive myogenic integration of the transplanted cells in group 4 with attenuated infarct size and improved cardiac function without tumorgenesis. Conclusions: Successful reprogramming was achieved in SMs with ES cell-like microRNA profile. Given the tumorgenic nature of SiPS, their predifferentiation into cardiomyocytes would be important for tumor-free cardiogenesis in the heart.

Original languageEnglish (US)
Pages (from-to)60-70
Number of pages11
JournalCirculation research
Volume109
Issue number1
DOIs
StatePublished - Jun 24 2011
Externally publishedYes

Keywords

  • heart
  • iPS cells
  • infarction
  • pluripotent
  • predifferentiation
  • reprogramming
  • tumor formation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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