Establishment of stably expandable induced myogenic stem cells by four transcription factors

Cell Death Dis. 2018 Oct 25;9(11):1092. doi: 10.1038/s41419-018-1114-8.

Abstract

Life-long regeneration of healthy muscle by cell transplantation is an ideal therapy for patients with degenerative muscle diseases. Yet, obtaining muscle stem cells from patients is very limited due to their exhaustion in disease condition. Thus, development of a method to obtain healthy myogenic stem cells is required. Here, we showed that the four transcription factors, Six1, Eya1, Esrrb, and Pax3, converts fibroblasts into induced myogenic stem cells (iMSCs). The iMSCs showed effective differentiation into multinucleated myotubes and also higher proliferation capacity than muscle derived stem cells both in vitro and in vivo. The iMSCs do not lose their proliferation capacity though the passaging number is increased. We further isolated CD106-negative and α7-integrin-positive iMSCs (sort-iMSCs) showing higher myogenic differentiation capacity than iMSCs. Moreover, genome-wide transcriptomic analysis of iMSCs and sort-iMSCs, followed by network analysis, revealed the genes and signaling pathways associated with enhanced proliferation and differentiation capacity of iMSCs and sort-iMSCs, respectively. The stably expandable iMSCs provide a new source for drug screening and muscle regenerative therapy for muscle wasting disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cell Cycle Checkpoints
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Cellular Reprogramming*
  • Dystrophin / metabolism
  • Female
  • Fibroblasts / metabolism*
  • Induced Pluripotent Stem Cells / metabolism*
  • Integrin alpha Chains / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL / embryology
  • Mice, Inbred mdx
  • Mice, Nude
  • Muscle Development
  • Muscular Dystrophies / therapy
  • Myoblasts / metabolism*
  • Pregnancy
  • RNA, Messenger / genetics
  • Stem Cell Transplantation
  • Transcription Factors / metabolism*
  • Transplantation, Autologous
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Antigens, CD
  • Dystrophin
  • Integrin alpha Chains
  • RNA, Messenger
  • Transcription Factors
  • Vascular Cell Adhesion Molecule-1
  • integrin alpha7