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Keywords:

  • Adult stem cells;
  • Tissue-specific stem cells;
  • Tissue regeneration;
  • Stem cell-microenvironment interactions;
  • Cell signaling;
  • Cardiac differentiation;
  • Endothelial differentiation;
  • Angiogenesis

Abstract

Mechanical cues can have pleiotropic influence on stem cell shape, proliferation, differentiation, and morphogenesis, and are increasingly realized to play an instructive role in regeneration and maintenance of tissue structure and functions. To explore the putative effects of mechanical cues in regeneration of the cardiac tissue, we investigated therapeutically important cardiosphere-derived cells (CDCs), a heterogeneous patient- or animal-specific cell population containing c-Kit+ multipotent stem cells. We showed that mechanical cues can instruct c-Kit+ cell differentiation along two lineages with corresponding morphogenic changes, while also serving to amplify the initial c-Kit+ subpopulation. In particular, mechanical cues mimicking the structure of myocardial extracellular matrix specify cardiomyogenic fate, while cues mimicking myocardium rigidity specify endothelial fates. Furthermore, we found that these cues dynamically regulate the same molecular species, p190RhoGAP, which then acts through both RhoA-dependent and independent mechanisms. Thus, differential regulation of p190RhoGAP molecule by either mechanical inputs or genetic manipulation can determine lineage type specification. Since human CDCs are already in phase II clinical trials, the potential therapeutic use of mechanical or genetic manipulation of the cell fate could enhance effectiveness of these progenitor cells in cardiac repair, and shed new light on differentiation mechanisms in cardiac and other tissues. Stem Cells 2014;32:1999–2007