Rap1/NF-kB信号调控间充质干细胞的免疫调节特性、机制以及应用于器官移植的研究

Adult bone marrow derived mesenchymal stem cells (BM-MSCs) have been well recognized as a promising cellular immune-modulator. However, the limited proliferative capacity, large variability and loss of stem cell potential in aged or diseased donor have hindered clinical application of BM-MSCs widely. .We have successfully derived MSCs from human pluripoten stem cells (including ESCs and iPSCs) . These ESC/iPSC-MSCs have overcome above limitations and display a greater potential in immune-modulation. However, the underlying mechanisms regulating MSC-mediated immune-modulation are little understood. .Our preliminary studies have unexpectedly shown the telomeric protein Rap1 mediated NF-κB signaling pathway acts as a central role in controlling cytokine profiles of MSC-mediated immune-modulation. Accordingly,we propose to study the roles and mechanisms of Rap1/NF-κB signaling in regulation of immunomodulation properties in MSCs. We will genetically elucidate the roles of Rap1 /NF-κB pathway in regulating functions of T cell, B cell, DC and Treg lymphocytes, through gain- and loss-of-function approaches in both mouse and human derived BM-MSCs and ESC/iPSC-MSCs. The roles of Rap1/NF-κB signaling in regulation of MSC immune-modulations will be verified in vivo by allo-heart and islet transplantations in mice. .These studies not only will provide new insight into the roles and mechanisms of Rap1/NFκB pathway in MSC-mediated immune-modulation, but also will lay down the bases for the development of therapeutic targets to reduce graft-versus-host-disease (GVHD) during organ or tissue transplantation.

成体来源BM-MSCs的免疫抑制特性已经被广泛的研究，但由于来源受限、细胞扩增衰老快、细胞质量批间差异大等缺点限制了其进一步的研究和临床应用。本课题组从多能干细胞诱导分化而来的ES-MSCs和iPS-MSCs可以很好的克服上述缺点，并且比BM-MSC有更大的治疗优势。明确其免疫抑制特性及调控机制尤其重要。在获得ES-MSCs和iPS-MSCs具有免疫抑制特性的初步数据后，我们认为端粒蛋白Rap1/NF-κB信号通道是调控MSCs免疫特性的关键分子生物学机制。本研究拟通过基因敲除动物和细胞模型，观察Rap1/NF-κB信号通道在控制BM/ESC/iPS-MSCs对T细胞、B细胞、DC细胞的增殖、活化及分化发挥调节功能的作用机制，以及对同种异体心脏移植物和胰岛移植物生存期的影响。通过本研究，我们力争阐明调控MSC免疫调节的分子生物学机制，为提高MSC的临床免疫治疗提供创新性的策略和理论依据。