To investigate the therapeutic mechanism of action of transplanted stem cells and develop exosome-based nanotherapeutics for ischemic stroke, we assessed the effect of exosomes (Exos) produced by human umbilical cord mesenchymal stem cells (hUMSCs) on microglia-mediated neuroinflammation after ischemic stroke. Our results found that injected hUMSC-Exos were able to access the site of ischemic damage and could be internalized by cells both in vivo and in vitro . In vitro , treatment with hUMSC-Exos attenuated microglia-mediated inflammation after oxygen-glucose deprivation (OGD). In vivo results demonstrated that treatment with hUMSC-Exos significantly reduced infarct volume, attenuated behavioral deficits, and ameliorated microglia activation, as measured three days post-transient brain ischemia. Furthermore, miR-146a-5p knockdown (miR-146a-5p k/d Exos) partially reversed the neuroprotective effect of hUMSC-Exos. Our mechanistic study demonstrated that miR-146a-5p in hUMSC-Exos reduces microglial-mediated neuroinflammatory response through IRAK1/TRAF6 pathway. We conclude that miR-146a-5p derived from hUMSC-Exos can attenuate microglia-mediated neuroinflammation and consequent neural deficits following ischemic stroke. These results elucidate a potential therapeutic mechanism of action of mesenchymal stem cells and provide evidence that hUMSC-Exos represent a potential cell-free therapeutic option for ischemic stroke.

Tumor initiating cells or cancer stem cells (CSCs) play an important role in the initiation, development, metastasis, and recurrence of tumors. However, traditional therapies have limited effects against CSCs and targeting these cells is crucial when developing new therapeutic strategies against cancer. One potentially targetable factor is CD47, a member of the immunoglobulin superfamily. This protein acts as an anti-phagocytic "don't eat me" signal and is often found expressed by cancer cells, particularly CSCs. CD47 functions by activating signal regulatory protein-α (SIRP-α) expressed on macrophages, preventing phagocytosis. However, the role of CD47 in glioma stem cells (GSCs) has been not been thoroughly investigated. Our study therefore examined the expression and function of this protein in glioma cells and GSCs. We found that CD47 was highly expressed on glioma cells, especially GSCs, and that expression associated with worse clinical outcomes. We also found that CD47+ glioma cells possessed stem/progenitor cell-like characteristics and knocking down CD47 expression resulted in a reduction in these characteristics. Treatment with anti-CD47 antibody led to increased phagocytosis of glioma cells and GSCs by macrophages. We next examined the effects of anti-CD47 antibody on glioma cells/GSCs in an immune competent mouse glioma model, revealing significant inhibition of tumor growth and prolonged survival times. Importantly, there were no apparent side effects in the animal model. In summary, we have shown that CD47 is a potentially safe and effective therapeutic target for glioma.

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.