Abstract P1075: Igf-1 Signaling And Nuclear Localization Of Pdgfralpha Tyrosine Kinase Activity Control The Fibrotic Response Of Mesenchymal Stromal Cells To Myocardial Ischemia

Abstract

Background and Hypothesis: The role of mesenchymal stromal cells expressing the platelet-derived growth factor alpha (PDGFRα + MSCs) has been associated with fibro-adipogenic pathologies. Based on our previous data in regenerating skeletal muscle and the data herein described, we hypothesized that specific and distinct mesenchymal stromal cells exist in the heart, which will retain regenerative capacities by modulating the spatiotemporal distribution of the PDGFRα tyrosine kinase activity and the re-expression of specific regenerative molecules. Methods: Myocardial ischemia/reperfusion (I/R) was induced in mice with standard procedures and in compliance with the regulations of the NIH and the local institutional animal care. Results: Confocal imaging and immunophenotyping analyses showed that cardiac PDGFRα + MSCs exist as two distinct sub-populations expressing markers of specialized and differentiated cells, such as endothelial (60.3%±7.9% expressing CD31) and cardiomyocyte cell-cell anchoring markers (89%± 0.6% of population expressing desmocollin 2/3), while also retaining the expression of mesenchymal markers. Importantly, whereas PDGFRα + MSCs organized in vessel-like structures expressing CD31 during the acute phase after I/R, they transitioned into myofibroblast-like cells in ischemic subacute conditions. Identifying the mechanisms regulating PDGFRα + MSCs dual function remains a critical roadblock. In addressing this gap, we discovered that the transition to myofibroblast-like cells was associated to nuclear shuttling of PDGFRα C-terminal tyrosine kinase domain and ligand-dependent increased nuclear area, suggesting receptor-mediated activation of chromatin remodeling. Furthermore, we discovered that therapeutic re-expression of downregulated paracrine factors, such as the IGF-1Ea splice variant, correlated with long-term organization of PDGFRα + /CD31 + in small capillaries, overcoming the late ischemic transition to fibrotic cells. Conclusions: Taken together, these data suggest that by modulating PDGFRα intracellular shuttling or altering the expression of regenerating genes, may therapeutically direct PDGFRα + MSCs duality to reduce fibrosis, while harnessing their beneficial properties.