Abstract 12: Physiological Role of Endogenous Adult Cardiac Colony-forming Unit Fibroblasts

Colony-forming unit fibroblasts (CFU-Fs), analogous to those giving rise to bone marrow (BM) mesenchymal stem cells (MSCs), have been identified in different tissues. CFU-Fs are multipotent progenitor cells, with a supportive paracrine and immunomodulatory function. They share the expression of surface antigens, are capable of self-renewal, and to differentiate into osteogenic, adipogenic and chondrogenic lineages in vitro. Our laboratory has isolated, for the first time, CFU-Fs from the adult murine heart. These cells are included within the Sca1+ PDGFRα+ CD31- fraction of interstitial cells, mainly associated with microvessels and the perivascular adventitial niche of larger vessels. Here we show that resident cCFU-Fs, are quiescent in homeostatic conditions, relatively more hypoxic and have a lower metabolic profile compared to other interstitial cells. Treatment with PDGF-AB ligand stimulates cCFU-Fs to exit the quiescent state, potentially making them more responsive to mitogenic and differentiative factors. In a mouse with a H2B-eGFP fusion gene knocked-in the Pdgfrα locus, cCFU-Fs lay in the GFPhigh population. After myocardial infarction, a GFPmed population appears, which has partially lost the expression of Sca1 and PDGFRα proteins, and consists largely of activated myofibroblasts. Likely derived from cCFU-Fs or related stromal fraction, GFPmed cells are significantly reduced by inhibiting PDGFRα signalling and increased by systemic PDGF-AB treatment. Despite augmenting the GFPmed myofibroblasts-like population, short-term PDGF-AB treatment is beneficial, leading to reduced scar, and increased vascular density and ejection fraction. A crucial factor in cardiac repair is the fine balance between pro-inflammatory (type1) and pro-reparative/pro-angiogenic (type2) immune responses, which can be regulated by MSCs. interestingly PDGF-AB treatment seems to be associated with an earlier resolution of the type1 response at 5 days after MI, compared to controls. We hypothesize that the beneficial effects of short term PDGF-AB treatment are due to early activation of cCFU-Fs and stromal cells from quiescence, leading to enhanced pro-angiogenic, anti-apoptotic and immunomodulatory impacts.