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

Abstract

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 1α (Hif-1α) could enhance the survival of the implanted BMSCs. BMSCs were isolated from Wistar rats, and were infected with Hif-1α-GFP lentiviral vector or Hif-1α 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-1α 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-1α overexpression protected OGD induced injury by promoting cellular viability and inhibiting apoptosis. AMPK was activated while mTOR was inactivated by Hif-1α overexpression, and that might be through which Hif-1α functioned BMSCs survival. Hif-1α overexpression promoted autophagy; more important, compound C abolished the induction of Hif-1α on autophagy. Transplantation of the overexpressed Hif-1α 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-1α might be contributed in the survival of BMSCs by regulating the activation of AMPK and mTOR, as well as by promoting autophagy.

Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System

“…The AMPK inhibitor, compound C, was purchased from Millipore (Merck, Billerica, MA, USA), and the dose of compound C was 20 μ Μ [ 19 , 20 ]. Compound C was added into the system for 24 hours after coculture for 8 days.…”

Strategies to retain properties of bone marrow–derived mesenchymal stem cellsex vivo

“…In this signaling pathway, PI3K and AKT can activate the mechanistic target of rapamycin (mTOR) and its downstream molecule HIF‐1α or suppress forkhead box protein O (FOXO) as well as downstream reactive oxygen species. Several groups have demonstrated that the PI3K/AKT/mTOR and the PI3K/AKT/FOXO3a signaling pathways are associated with MSC survival in culture or animal models . It has also been demonstrated that activation of the PI3K/AKT signaling pathway is critical to increasing hypoxia‐induced proliferation and differentiation of MSCs into ECs …”

A Novel Method for Screening the Effective Compatibility Fractions of Naomaitong for the Treatment of Cerebral Ischemic Stroke Using Support Vector Machine Model

“…Infarct area evaluation [22,23] After h of perfusion, rats were anesthetized with 7% chloral hydrate. The brain was isolated and cut into 2-mm-thick slices.…”