Hypoxia promotes a perinatal-like progenitor state in the adult murine epicardium

Abstract

The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex single cell transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal cells, as well as cells with an endothelial-like fate. We found that physiological hypoxia promoted a perinatal-like progenitor state in the adult murine epicardium. In vitro clonal analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and multilineage differentiation potential. These results point to a source of progenitor cells in the adult heart that can be stimulated in vivo and provide an in vitro model for further studies.

Targeting the redox system for cardiovascular regeneration in aging

“…Activation of HIF-1α in CPCs promotes angiogenesis, inhibits apoptosis, and enhances their regenerative capacity. These may drive cardiac tissue turnover during normal aging and post-myocardial injury (Sayed et al, 2022).…”

“…Activation of HIF‐1α in CPCs promotes angiogenesis, inhibits apoptosis, and enhances their regenerative capacity. These may drive cardiac tissue turnover during normal aging and post‐myocardial injury (Sayed et al., 2022 ). However, dysregulation of HIF‐1α signaling in aging impairs the responsiveness of CPCs to hypoxia, leading to compromised cardiac repair mechanisms.…”

The Regulatory Roles of Mitochondrial Metabolism Dynamics and Mitochondria Calcium Uniporter (MCU) in Bevacizumab Resistance of GBM

“…Since MCU and SQOR have commercially available specific inhibitors, we evaluated the cytotoxicity of the MCU‐specific inhibitor DS16570511 and the SQOR‐specific inhibitor CPI‐613 on U87MG cells under normoxia (22% oxygen) or hypoxia (1% oxygen) conditions (Data not shown), mimicking the hypoxic tumor microenvironment affected by bevacizumab in vivo. [ 16 ] The U87MG cells were seeded and treated with inhibitors at doses ranging from 5 to 20 µ m for 72 h. The luminescence of living cells was measured by detecting ATP, which is a signal of metabolically active cells. The results of the proliferation assay showed that DS16570511 significantly inhibited cell proliferation under hypoxic conditions compared to normoxic conditions.…”

ScRNA-seq and spatial transcriptomics: exploring the occurrence and treatment of coronary-related diseases starting from development

“…Studies have shown that adult epicardial cells exposed to chronic hypoxia have developmental characteristics similar to the endothelial-mesenchymal transformation at the embryonic stage. They can differentiate into various cell types and promote coronary angiogenesis in a paracrine manner ( 66 – 68 ). To explore the role of endothelial-mesenchymal transition in the epicardium after myocardial infarction in angiogenesis, single-cell sequencing and RNA multiplex fluorescence in situ hybridization were combined ( 17 ).…”