Human Umbilical Cord Mesenchymal Stem Cells Protect Ischemic Stroke By Regulating Neuron-microglia Crosstalk

Background:Ischemic stroke is a leading cause of morbidity and mortality worldwide. At present, there are few clinically- validated treatments for stroke patients. Ischemic brain injury results from a cascade of events initiated by energy depletion and culminating in cell death. Contributing factors in this cascade include glutamate excitotoxicity, oxidative stress, and inflammation. Inflammation requires longer time to fully develop, and is a key regulator for neuronal survival ant later neural restoration. Therefore, post-stroke inflammation is a much more practical target for treating a large fraction of stroke patients. Using stem cells to treat ischemic stroke has drawn extensive attention. Stem cells not only can differentiate into neurons, glia and endothelial cells for neural restoration, but also can regulate critical post-stroke events including inflammation, neurogenesis and immune response. Stem cells exert neuroprotection via several mechanisms depending on differences in ischemic stroke and the patterns and timing of stem cells intervention.Purpose:Previous studies have shown that human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) can inhibit post-stroke peripheral immune inflammation. This study will further investigate roles of hUC-MSCs in modulating microglial activation, and aim to provide theoretical basis for clinical application.Methods:ICR mice were randomly designated into sham, MCAO+NS and MCAO+ hUC-MSCs group. MCAO ischemia-reperfusion (90min) was established. NS or hUC-MSCs were administrated via caudal vein 30min after reperfusion. mNSS, brain water content and TTC were examined 24h,72h and 1w after reperfusion, which were used to evaluate neurological deficit, brain swell and infarct volume. mRNA levels of anti-inflammatory and pro-inflammatory factors were measured by Q-PCR. Expression of CD200,CD200R and CCL21,CXCR3 was examined by Q-PCR and immunofluorescence.Results:1. hUC-MSCs exert neuroprotection in ischemic stroke; 2. hUC-MSCs can alleviate brain inflammation after stroke; 3. hUC-MSCs can inhibit post-stroke microglial activation; 4. hUC-MSCs affect microglial activation by regulating neuron-microglia crosstalk; 5. hUC-MSCs may regulate neuronal expression of CD200 and CCL21 by IL-4 and TWEAK, respectively.Conclusions:hUC-MSCs protect ischemic stroke by regulating neuron-microglia crosstalk and inhibiting microglial activation.