Concise review: Mechanotransduction via p190RhoGAP regulates a switch between cardiomyogenic and endothelial lineages in adult cardiac progenitors.
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.
Department of Bioengineering, Institute of Stem Cells and Regenerative Medicine and Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA; Institute of Stem Cells and Regenerative Medicine and Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA.
Kshitiz
Junaid
J
Afzal
Deok-Ho
DH
Kim
Andre
A
Levchenko
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*
C074560:ARHGAP35 protein, human; D020662:Guanine Nucleotide Exchange Factors; D012097:Repressor Proteins
Adult stem cells; Angiogenesis; Cardiac differentiation; Cell signaling; Endothelial differentiation; Stem cell-microenvironment interactions; Tissue regeneration; Tissue-specific stem cells