Transplantation of Roxadustat-preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats

Abstract

Aims: The therapeutic effect of bone marrow stromal cell (BMSC) transplantation for ischemic stroke is limited by its low survival rate. The purpose of this study was to evaluate whether Roxadustat (FG-4592) pretreatment could promote the survival rate of grafted BMSCs and improve neurological function deficits in ischemia rats. Methods: Oxygen–glucose deprivation (OGD) and permanent middle cerebral artery occlusion (pMCAO) were constructed as stroke models in vitro and in vivo. Flow cytometry analysis and expression of Bax and Bcl-2 were detected to evaluate BMSCs apoptosis. Infarct volume and neurobehavioral score were applied to evaluate functional recovery. Inflammatory cytokine expression, neuronal apoptosis, and microglial M1 polarization were assessed to confirm the enhanced neurological recovery after FG-4592 pretreatment. Results: FG-4592 promoted autophagy level to inhibit OGD-induced apoptosis through HIF-1α/BNIP3 pathway. GFP and Ki67 double staining showed an improved survival rate of BMSCs in the FG-4592 group, whereas infarct volume and neurobehavioral score verified its enhanced neurological recovery activity simultaneously. NeuN and Iba-1 fluorescence staining showed improved neural survival and decreased microglial activation, along with decreased IL-1β, IL-6, and TNF-α levels through the TLR-4/NF-kB pathway. Conclusions: FG-4592 pretreated BMSCs improve neurological function recovery after stroke and are likely to be a promising strategy for stroke management.