Abstract 16139: Mast Cells Promote Proliferation and Suppress Myogenic Differentiation of Mesenchymal Stem Cells
Introduction: Efficient scar formation post-myocardial infarction (MI) depends on fibroblast/mesenchymal stem cell (MSC) accumulation and myofibroblast transdifferentiation. Mast cell (MC)-deficient mice exhibit reduced cardiac myofibroblast accumulation and undergo rapid left ventricular dilation post-MI. Thus, we sought to investigate how MCs modulate MSC proliferation and their myogenic differentiation into myofibroblasts.
Methods: MC/MSC co-culture was used to examine MC effects on MSC proliferation and differentiation. MC granulate (MCG) was then used to further examine the mechanisms by which MCs exerted their effects on MSC proliferation, migration, and myogenic differentiation. The effects of MCs on MSC activity in vivo was evaluated by immunohistological analysis on MC- and saline-treated infarcted mouse hearts at 3 and 7 days post-MI
Results: MC co-culture suppressed expression of the myogenic differentiation marker α-smooth muscle actin in MSCs. Similarly, MCG dose-dependently decreased myogenic differentiation by up to ~90% (P<0.01, n=4) and increased MSC proliferation ~two-fold (P<0.01, n=5) and migration by ~75% (P<0.01, n=4). Pharmacological antagonism of platelet-derived growth factor receptor (PDGFR) rescued MSC differentiation despite MCG treatment, suggesting MC suppression of MSC differentiation occurs through PDGFR. MCG treatment resulted in up to ~70% decreased miR-145 and -143 expression (P<0.05, n=4), as well as increased Klf4 (~25%) and decreased myocardin (~50%) protein expression in MSCs, indicating that the myocardin-Klf4 axis mediates MSC proliferation/differentiation. Finally, infarcted hearts from mice treated with MCs showed ~five-fold increased CD29+ MSC proliferation at day 3 vs saline-treated animals (P<0.05, n=3). This effect was absent by day 7 post-MI.
Conclusions: MSCs can oscillate between proliferative and differentiated states. MCs promote proliferation at the expense of differentiation early after MI through PDGFR, downregulation of miR-145 and -143, and the Klf4-myocardin signalling axis to promote MSC accumulation. This in turn results in a larger cardiac MSC pool for later myofibroblast differentiation, facilitating improved wound healing.
Author Disclosures: M. Nazari: None. N.C. Ni: None. A.L. Ludke: None. S. Li: None. J. Guo: None. T.M. Yau: None. R.D. Weisel: None. R. Li: None.
- © 2015 by American Heart Association, Inc.