The effect of hypoxic stress on cardiac stem cell proliferation

Stem cells capable of self-renewal and regeneration of cardiac tissue (CSCs) have been identified in the adult heart. Evidence suggests that CSCs are damaged during myocardial infarction (MI) losing their potential to repair the heart after injury. Clarification of the mechanisms involved in CSC response to damage is essential to protect their regenerative potential and improve stem cell therapy.

Hypoxia is a hallmark occurrence during MI. Using gene expression profiling we found that the expression of several adhesion molecules is down-regulated in hypoxia-exposed CSCs. Integrin-β1 (Itgb1) is highly expressed in CSCs and has been shown to be required for stem cell interactions within their niche. Accordingly, we hypothesized that hypoxia damages CSCs by loosening their interaction with extracellular-matrix through down-regulation of Itgb1.

Time-course analysis of CSCs grown under normoxic and hypoxic conditions showed significant reduction in proliferation rate by approximately 40% (p<0.05) 2-4 days after hypoxia, which correlated with down-regulation of Itgb1 expression by 30% (p<0.007). We have generated stable Itgb1-deficient CSCs using RNA interference, which are currently being tested for proliferation, adhesion, differentiation and survival. We conclude that hypoxic stress affects CSCs proliferation and that these changes are associated with down-regulation of Itgb1.