电针调控A2星形胶质细胞促进移植NSC源性神经元与损伤脊髓的神经元形成突触的机制研究

我们研究证实督脉电针(EA)促进移植的神经干细胞(NSC)源性神经网络与损伤脊髓神经网络整合，但EA促进移植神经元与宿主神经元形成突触的机制尚不明确。最近实验显示，EA促进脊髓损伤(SCI)活化的M1小胶质细胞转化为抗炎的M2型，降低TNF-α而提高IL-4，激活IL-4/STAT6通路，并伴有神经毒性A1星形胶质细胞(A1s)减少。研究表明，A1s可损害神经元和突触，而前动力蛋白(PK2)激活STAT6诱导A1s转为A2星形胶质细胞(A2s)促进修复。因此，本研究假设：EA促使损伤脊髓内M2小胶质细胞分泌IL-4和PK2，协同激活STAT6通路诱导神经毒性A1s逆转为神经修复性A2s，分泌促突触形成分子，促进移植神经元与宿主神经元形成突触。本研究旨在前期工作基础上探明EA调控A2s形成及其介导移植神经元与宿主神经元形成突触的关键分子机制，为EA联合干细胞治疗SCI的临床转化提供理论依据。

Our study has confirmed that Governor Vessel electro-acupuncture (EA) promotes the integration of transplanted neural stem cells (NSC) -derived neural network with the neural network of injured spinal cord, but it remains unclear to the mechanism of EA promoting the synapse formation between transplanted neurons and host neurons. Our recent experiments found that EA promoted spinal cord injury (SCI) activating M1 microglia shift into anti-inflammatory M2 microglia, decreased TNF-α and increased IL-4, activated the IL-4R/STAT6 signal pathway, which was accompanied with the reduction of A1 astrocytes (A1s). Studies have indicated that the neurotoxic A1s damage neurons and synapses. Prokineticin-2 (PK2) activates STAT6 to induce A1s switch A2 astrocytes (A2s) which promote neural repair. Therefore, this study hypothesizes that EA could enhance M2 microglia in the injured spinal cord to secrete IL-4 and PK2, and then synergistically activated the STAT6 pathway by binding with their receptors to induce the neurotoxic A1s switch to neuroprotective A2s, and further A2s secrete some synaptogenesis molecules to promote the formation of synaptic connections between NSC-derived neurons and host neurons of injured spinal cord. On the basis of our previous research work, this study will elucidate the key molecular mechanisms of EA regulating the A2s formation and A2s facilitating synaptic formation between grafted neurons and host neurons, and provide the theoretical and experimental evidence for the clinical transformation of electro-acupuncture combined with stem cell therapy for SCI.