多系分化持续应激细胞治疗小鼠神经病理性疼痛的作用及机制

神经病理性痛是常见难治性疾病，我们之前发现椎管内注射骨髓间充质干细胞（BMSCs）能长期缓解神经病理性痛小鼠的痛觉过敏，这有可能为治疗提供了新方法。然而BMSCs是一群细胞，包含多种亚类，是哪一类或几类细胞亚群发挥着镇痛作用还不清楚，在培养过程中各细胞亚类的比例也会不断发生变化，BMSCs的镇痛能力在传代多次后也出现显著减弱。这些制约了BMSCs作为商品化的镇痛药物的临床开发。多系分化持续应激细胞（Muse细胞）是在BMSCs中发现的一类亚型，单细胞可成细胞球、遗传稳定性好、免疫排斥性低。我们预实验发现注射Muse细胞可以缓解小鼠的神经病理性痛。本课题将从基因、分子、细胞、组织及动物行为等多个层面，对椎管内移植Muse细胞治疗神经病理性痛的效果和机制开展研究，目的在于从间充质干细胞中寻找安全、稳定、镇痛能力持久的单一细胞亚群，从而突破制约神经病理性疼痛的间充质干细胞疗法临床应用的瓶颈。

Treatment of neuropathic pain triggered by multiple insults to the nervous system is a clinical challenge. Unfortunately, current treatments for neuropathic pain are insufficient. More and more evidence has shown that transplantation of bone marrow stromal cells/bone marrow mesenchymal stem cells (BMSCs) can relieve neuropathic pain. In our recent paper, we demonstrated a paracrine mechanism by which intrathecal bone marrow stromal cells/bone marrow mesenchymal stem cells (BMSCs) target CXCL12-expressing DRGs to produce long-term (>5 weeks) relief of neuropathic pain via TGF-β1 secretion. The intrathecal route of BMSC delivery is safe and several clinical trials show that intrathecal injection of BMSCs does not cause adverse health issues over 12 months following injection. The intrathecal route can target a common pain pathway, ensure long-term survival of BMSCs, and provide long-term pain relief. Therefore, intrathecal injections of BMSCs may provide efficient, long-term, safe, and inexpensive treatment for chronic pain. However, BMSCs are heterogeneous, and their entire composition is not fully identified. And this can cause a lot of problems in the standardized clinical application. Multilineage-differentiating stress-enduring (Muse) cells, which were first reported in 2010, correspond to just several percent of the BMSCs. Muse cells are a homogenous cell subgroup in BMSCs and can be efficiently isolated as cells positive for both SSEA-3 and CD105. Muse cells exhibit multipotency, high proliferation activity and do not form teratomas in immunodeficient mice. At present, the study of Muse cells is mainly focused on their differentiation ability and whether Muse cells can be used to treat neuropathic pain is unknown. Our preliminary results have been shown that intrathecal injection of human Muse cells can reduce neuropathic pain in various mouse models, including nerve injury, diabetes and chemotherapy induced neuropathic pain. In this application, we will carry out in-depth study of intrathecal Muse cells treatment of neuropathic pain, including 1) analgesic effects of Muse cells in the model of neuropathic pain in mice 2) the mechanisms of Muse cells treat neuropathic pain. Our results may provide a new method for the treatment of neuropathic pain in future clinical trials.