HIF-1α inhibits mitochondria-mediated apoptosis and improves survival of human adipose-derived stem cells in ischemic microenvironments

Summary Background: Human adipose mesenchymal stem cells (hADSCs) show poor survival after transplantation, limiting their clinical application. Tissue regeneration resulting from stem cell treatment may be caused by attenuation of hypoxia inducible factor-1 α (HIF-1α). In this study, we constructed hADSCs stably expressing HIF-1α and investigated the potential effects of HIF-1α expression in the ischemic microenvironment on mitochondrial apoptosis and survival of hADSCs, and studied the mechanisms involved. Method: Apoptosis was induced by an ischemic microenvironment in vitro. ADSCs with stable HIF-1α expression were established. Cell survival and apoptosis were observed by CCK-8 assay, western blotting, flow cytometry, and fluorescence staining. ADSCs were subcutaneously transplanted into nude mice in the location where a hypoxia ischemic microenvironment was simulated in vivo. After 1, 3, and 7 d, mitochondrial apoptotic proteins were evaluated by immunohistochemistry and immunofluorescence staining. Results: Exogenous HIF-1α downregulated mitochondrial reactive oxygen species, cytochrome c, caspase-9 and caspase-3, but inhibited mitochondrial membrane potential depolarization and increased the Bcl-2/bax ratio. HIF-1α prevented apoptosis and promoted VEGF secretion as demonstrated by ELISA, TUNEL staining and flow cytometry analysis. HIF-1α enhanced the survival of transplanted ADSCs in nude mice. Conclusion: We have shown that through inhibition of the mitochondria-mediated apoptotic pathway, and promotion of VEGF secretion in hADSCs in a ischemic microenvironment, HIF-1α may potentially be applied in clinical therapy and as an alternative strategy for improving hADSC therapy.