Hypoxia Protects Rat Bone Marrow Mesenchymal Stem Cells Against Compression-Induced Apoptosis in the Degenerative Disc Microenvironment Through Activation of the HIF-1 alpha/YAP Signaling Pathway

摘要

Stem cell therapy provides an attractive solution for intervertebral disc (IVD) degeneration. However, the degenerative microenvironment, characterized by excessive mechanical loading and hypoxia, remains an obstacle for the long-lasting survival of exogenous transplanted stem cells. Whether and how bone marrow mesenchymal stem cells (BMSCs) adapt to the hostile microenvironment remain unclear. In this study, CoCl2 and mechanical compression were simultaneously used to simulate the hypoxic and overloaded microenvironment of IVDs in vitro. Compression had a proapoptotic effect through activation of the mitochondrial apoptotic pathway, while hypoxia exerted a prosurvival effect counteracting compression-induced apoptosis. Inhibiting the transcriptional activity of hypoxia inducible factor 1 subunit alpha (HIF-1 alpha) by chetomin reversed the antiapoptotic effect of hypoxia. Furthermore, HIF-1 alpha promoted dephosphorylation and activation of yes-associated protein (YAP) in hypoxic conditions. Conversely, both YAP inhibition and increased cell apoptosis were observed after inhibition through chetomin or YAP inhibitor verteporfin. Immunofluorescence staining and coimmunoprecipitation assays revealed that YAP could interact directly with HIF-1 alpha and colocalize in the nucleus. Taken together, our results demonstrated that hypoxia protected BMSCs against compression-induced apoptosis in the degenerative disc microenvironment through activation of the HIF-1 alpha/YAP signaling pathway. Thus, regulation of HIF-1 alpha/YAP signaling might provide novel insights for promoting long-lasting BMSC survival and optimizing stem cell therapy for IVD degeneration.