Low oxygen tension positively influences cardiomyocyte progenitor cell function

Previously we observed that cardiomyocyte progenitor cells (hCMPCs) isolated from the human heart differentiate spontaneously into cardiomyocytes and vascular cells when transplanted after myocardial infarction (MI) in the ischemic heart. After MI, deprivation of oxygen is the first major change in the cardiac environment. How cells handle hypoxia is highly cell type dependent. The effect of hypoxia on cardiac stem or progenitor cells remains to be elucidated. Here, we show for the first time that short- and long-term hypoxia have different effects on hCMPCs. Short-term hypoxia increased the migratory and invasive capacities of hCMPCs likely via mesenchymal transformation. Although long-term exposure to low oxygen levels did not induce differentiation of hCMPCs into mature cardiomyocytes or endothelial cells, it did increase their proliferation, stimulated the secretome of the cells which was shifted to a more anti-inflammatory profile and dampened the migration by altering matrix metalloproteinase (MMP) modulators. Interestingly, hypoxia greatly induced the expression of the extracellular matrix modulator thrombospondin-2 (TSP-2). Knockdown of TSP-2 resulted in increased proliferation, migration and MMP activity. In conclusion, short exposure to hypoxia increases migratory and invasive capacities of hCMPCs and prolonged exposure induces proliferation, an angiogenic secretion profile and dampens migration, likely controlled by TSP-2.