HIF-1<alpha> Repression of PTEN Transcription Mediates Protective Effects of BMSCs on Neurons During Hypoxia.

Neonatal hypoxic-ischemic brain damage (HIBD) is a cerebral hypoxic-ischemic disease caused by a variety of insults during the perinatal period, leading to varying degrees of cognitive dysfunction. Mesenchymal stem cells play an important role in functional recovery, but the mechanism is not yet clear. It has been reported that HIF-1<alpha> and PTEN are involved in the process of hypoxia-ischemia, but the specific roles that these proteins play remains to be understood. In this study, we performed oxygen glucose deprivation (OGD) or CoCl2 preconditioning on hippocampal neurons to simulate a hypoxic environment in vitro, and then co-cultured them with BMSCs, to observe the effect of BMSCs and the role of HIF-1<alpha>. In addition, bpV, an inhibitor of PTEN was added to OGD neurons to determine the role of PTEN during hypoxia. We found that the levels of cell damage and apoptosis in OGD neurons decreased significantly after co-culture with BMSCs. Apoptosis was increased when HIF-1<alpha> was inhibited, but neurons remained protected when PTEN was suppressed. We further established that HIF-1<alpha> was enriched at the PTEN promoter both in BMSCs and hippocampal neurons, with increased enrichment under hypoxic conditions, leading to reduced transcription of PTEN. Our findings support the conclusion that CoCl2 preconditioning of BMSCs can simulate hypoxic conditions and can protect OGD neurons, an effect that is mediated through activation of the HIF-1<alpha> system and repression of PTEN transcription.