Abstract
Early-stage mammalian embryos survive within a low oxygen tension environment and develop into fully functional, healthy organisms despite this hypoxic stress. This suggests that hypoxia plays a regulative role in fetal development that influences cell mobilization, differentiation, proliferation, and survival. The long-term hypoxic environment is sustained throughout gestation. Elucidation of the mechanisms by which cardiovascular stem cells survive and thrive under hypoxic conditions would benefit cell-based therapies where stem cell survival is limited in the hypoxic environment of the infarcted heart. The current study addressed the impact of long-term hypoxia on fetal Islet-1+ cardiovascular progenitor cell clones, which were isolated from sheep housed at high altitude. The cells were then cultured in vitro in 1% oxygen and compared with control Islet-1+ cardiovascular progenitor cells maintained at 21% oxygen. RT-PCR, western blotting, flow cytometry, and migration assays evaluated adaptation to long term hypoxia in terms of survival, proliferation, and signaling. Non-canonical Wnt, Notch, AKT, HIF-2α and Yap1 transcripts were induced by hypoxia. The hypoxic niche environment regulates these signaling pathways to sustain the dedifferentiation and survival of fetal cardiovascular progenitor cells.
Highlights
Cardiovascular progenitor cells (CPCs) have been evaluated for numerous applications to treat a variety of cardiovascular diseases from congenital heart defects to myocardial infarctions [1,2]
We demonstrate the involvement of these pathways in the hypoxic niche and suggest a potential interconnected pathway that maintains the survival of dedifferentiated cardiovascular progenitor cells through the upregulation of the PI3K/AKT pathway by Notch, non-canonical wingless tyrosine kinase (Wnt), and FAK pathways
Islet-1 is a known marker of early lineage, multipotent CPCs
Summary
Cardiovascular progenitor cells (CPCs) have been evaluated for numerous applications to treat a variety of cardiovascular diseases from congenital heart defects to myocardial infarctions [1,2] This population of cells is capable of differentiating into the three cardiac lineages: cardiomyocytes, endothelial, and vascular smooth muscle cells. Hypoxia inducible factors, HIF-1α and HIF-2α, have been evaluated to determine their involvement in dedifferentiation and survival These pathways regulate survival, proliferation, migration, and differentiation and play roles in fetal development, which ties them to hypoxic regulation. We demonstrate the involvement of these pathways in the hypoxic niche and suggest a potential interconnected pathway that maintains the survival of dedifferentiated cardiovascular progenitor cells through the upregulation of the PI3K/AKT pathway by Notch, non-canonical Wnt, and FAK pathways
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