Hif-1α Overexpression Improves Transplanted Bone Mesenchymal Stem Cells Survival in Rat MCAO Stroke Model

Bone mesenchymal stem cells (BMSCs) death after transplantation is a serious obstacle impacting on the outcome of cell therapy for cerebral infarction. This study was aimed to investigate whether modification of BMSCs with hypoxia-inducible factor 1 alpha (Hif-1 alpha) could enhance the survival of the implanted BMSCs. BMSCs were isolated from Wistar rats, and were infected with Hif-1 alpha-GFP lentiviral vector or Hif-1 alpha siRNA. The modified BMSCs were exposed to oxygen-glucose deprivation (OGD) condition, cellular viability and apoptosis were then assessed. An inhibitor of AMPK (compound C) was used to detect whether AMPK and mTOR were implicated in the functions of Hif-1 alpha on BMSCs survival. Besides, ultrastructure of BMSCs was observed and the expression of autophagy markers was measured. The modified BMSCs were transplanted into middle cerebral artery occlusion (MCAO) model of rats, and the cerebral infarction volume and neurological function was assessed. The results indicated that Hif-1 alpha overexpression protected OGD induced injury by promoting cellular viability and inhibiting apoptosis. AMPK was activated while mTOR was inactivated by Hif-1 alpha overexpression, and that might be through which Hif-1 alpha functioned BMSCs survival. Hif-1 alpha overexpression promoted autophagy; more important, compound C abolished the induction of Hif-1 alpha on autophagy. Transplantation of the overexpressed Hif-1 alpha of BMSCs into the MCAO rats reduced brain infarct volume and improved neurobehavioral outcome; besides, it inhibited pro-inflammatory cytokines generation while promoted neurotrophin secretion. In conclusion, Hif-1 alpha might be contributed in the survival of BMSCs by regulating the activation of AMPK and mTOR, as well as by promoting autophagy.