IL-10受体炎性信号在造血干细胞多潜能决定中的调控研究

Hematopoietic stem cells (HSCs) transplantation is an effective method to treat malignant hematopoietic disease and immune deficiency diseases. The main challenge is that the number of HSCs that can be used is insufficient, and HSCs that have long-term effects and totipotency have not yet been successfully prepared in vitro. To study the molecular mechanism of HSCs development in vitro and identify key cytokines of HSCs generation is an important basis for promoting its clinical treatment. Recent studies have shown that pro-inflammatory cytokines become key factors in the regulation of HSCs development. IL-10 is a very important inflammatory regulatory factor, and our preliminary work has confirmed that IL-10 signal is involved in the regulation of HSCs specification. Therefore, the regulation of IL-10 and its receptor signaling on HSCs development is worth exploring. This study will use embryonic stem cells-induced HSCs in vitro and transgenic and mutant animal models to illustrate the potential regulatory role of IL-10 and receptor in the process of HSCs specification and fate decision of myeloid and lymphoid. We will further reveal the molecular mechanism of IL-10 dependant HSCs development and recognize the inflammatory signaling network in the homeostasis maintenance of HSCs and fate decision. We will eventually establish the IL-10 dependant regulatory system of HSCs specification in vitro and enhance the immune potential of HSCs. The prospective aim of this study is to improve the cytokines formula of HSCs amplification in vitro, to improve the effect of transplantation using cultured HSCs, and to provide necessary theoretical reference of the use of immunosuppressants in the process of transplantation.

造血干细胞（HSCs）移植面临的主要挑战是HSCs来源缺乏，具有长效和全能性的HSCs尚未在体外成功制备。研究HSCs体外发育的分子机制，鉴定促进HSCs生成的细胞因子，是推动其临床应用的重要基础。最近研究表明，促炎症因子成为HSCs发育调节的关键因子。IL-10是重要的炎性调控因子，我们前期工作发现IL-10信号缺失导致HSCs的生成减少。因此，IL-10及其受体对HSCs发育的调控值得深入探讨。本研究将利用胚胎干细胞体外诱导HSCs体系及转基因和突变动物模型，阐明IL-10及受体在HSCs特化及淋髓系潜能决定中的调控作用，揭示其调控HSCs发生分化的分子机制，深入认识其调控HSCs稳态维持和命运决定中的信号网络，建立其体外调控HSCs特化体系和免疫功能潜力增强的新途径，完善体外对HSCs的扩增诱导因子组合，提高HSCs移植效果，并为移植过程中免疫抑制剂的使用提供参考。

炎性因子调控HSCs的生成或活化是近几年出现的研究热点，但是未知的内容很多。作为免疫炎性体系中的重要信号，IL-10及受体在HSCs多潜能调控中的作用未见报道。本研究已按照研究计划完成了项目研究。阐明了免疫炎性重要信号IL-10及受体在HSCs特化及淋髓系潜能决定进程中的调控作用。揭示了IL-10及受体调控HSCs发育分化的分子机制调控，绘制了其在炎性调控HSCs稳态维持和命运决定中的信号网络，建立其体外调控HSCs特化体系和免疫功能潜力增强的新途径。完善了体外对HSCs的扩增诱导因子组合，提高HSCs移植效果。为HSCs的体外保真性培养和扩增提供直接方案，为解决临床HSCT中HSCs不足的问题，并为移植过程中免疫抑制剂的使用影响提供了必要的理论参考。研究过程中取得具有国际影响的原创性成果，部分成果发表于2020年在Science Advances。