Abstract
Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, evidence suggests that their regenerative capacity may be limited in conditions of severe hypoxia. Elucidating the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential. We investigated the effects of hypoxic stress on CPCs and found significant reduction in proliferation and impairment of vasculogenesis, which were associated with induction of quiescence, as indicated by accumulation of cells in the G0-phase of the cell cycle and growth recovery when cells were returned to normoxia. Induction of quiescence was associated with a decrease in the expression of c-Myc through mechanisms involving protein degradation and upregulation of p21. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, also triggering quiescence. Surprisingly, these effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions.
Highlights
Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function
We investigated the effect of hypoxic stress on CPC proliferation
Cells were cultured under ischemic hypoxic (0.5% O2) and normoxic (21% O2) conditions, and proliferation estimated by counting cell numbers daily over a period of 96 hours
Summary
Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, triggering quiescence These effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions. Oxygen delivery through the vascular network is critical to prevent myocyte loss Despite their vasculogenic properties, resident CPCs are not able to promote sufficient revascularization after ischemic injury, suggesting that the hypoxic environment may impair their regenerative potential. Our results suggest that downregulation of c-Myc under ischemic injury may contribute to impairment of CPCs regenerative potential
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