Abstract 18959: Mesp1 Marked Cardiac Progenitor Cells Repair Infarcted Mouse Hearts
Mesp1 directs multipotential cardiovascular cell fates, even though it’s transiently induced prior to the appearance of the cardiac progenitor program. Because of Mesp1’s transitory nature, Mesp1-CPC lineages were traced by following EYFP expression in murine Mesp1Cre/+; Rosa26EYFP/+ ES cells. These earliest CPCs strongly expressed cardiac mesoderm markers (Flk1, PDGFRα, Hand2), cardiac transcription factors (Nkx2-5, Tbx5, Mef2c), but not pluripotent markers (Oct4, Sox2, Nanog) nor nascent mesoderm markers (T, Fgf8). These CPCs expressed miRNAs involved in early cell fate decisions but not those in terminal cardiomyocytes. The early EYFP+ cells represented a sub-population of the Flk1+/PDGFRα+ cells, which were widely used to isolate CPCs. BMPs, canonical Wnts and Activin were required for induction and accumulation of Mesp1-CPCs, but extended BMP4 was not compatible with cardiomyocyte formation. Meantime, canonical Wnt inhibitor IWR1 was sufficient to drive CPCs toward cardiomyocyte, suggesting drastic change of extracellular cues is essential for the switch from CPC specification to differentiation. In a post-myocardium infarction mouse model, injected Mesp1-CPCs differentiated into cardiac muscle cells, vascular smooth muscle cells and endothelial cells, with evident neovascularization in both infarct and border zones. Mesp1-CPC proliferation remained evident 12 weeks after injection into the post-MI murine hearts. Injected mouse pre-contractile Mesp-1/EYFP+ CPCs improved the survivability of injured mice and restored the functional performance of infarcted hearts for at least 3 months. In summary, Mesp1-EYFP+ cells are bona fide CPCs and they integrated well in infarcted hearts and emerged de novo into terminally differentiated cardiac myocytes, smooth muscle and vascular endothelial cells.
- © 2013 by American Heart Association, Inc.