Long-Term Hypoxia Maintains a State of Dedifferentiation and Enhanced Stemness in Fetal Cardiovascular Progenitor Cells

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.

Serial Gene Expression Profiling of Neural Stem Cells Shows Transcriptome Switch by Long-Term Physioxia from Metabolic Adaption to Cell Signaling Profile

“…Dll1, Dll3, or Hes5 as part of Notch signaling and downregulated in long-term physioxic midbrain NSC is known to be essential for neurogenesis and is predominantly described for maintenance of stem cell state and blocking of differentiation [70][71][72][73][74][75][76][77]. In long-term physioxic cortical NSCs, similar results were found regarding Notch signaling by downregulation of Dll1 or Hey2 [78,79]. Although most of these studies are only relevant for the cortical situation, they are conflicting with enhanced proliferation under hypoxia from previous reports [27].…”

Trends in research on sick sinus syndrome: A bibliometric analysis from 2000 to 2022

“…Tbx 18 gene was mainly involved in the development of the head of the SAN ( 68 ). ISL-1 was one of the molecular markers of undifferentiated cardiac histocytes/heart cells in the second cardiac region, which can promote cardiac development and differentiation ( 69 ). Study had found that mouse embryos with the ISL-1 gene knocked out had cardiac arrest or severe cardiac malformations at day 9.5 ( 70 ).…”