骨髓间充质干细胞与髓系抑制细胞相关性研究

To reveal mechanisms about the differentiation and final destination of bone marrow mesenchymal stem cells (BMSCs) infused into a host is a key problem that correlates with current BMSCs research.This project is based on the theory that BMSCs are applied in tissue repairing and immunoregulatory research. When a patient is infected or suffered from a tumor, BMSCs and myeloid derived suppressor cells (MDSCs) would be quickly mobilized from bone marrow and released into a peripheral tissue and subsequently both the BMSCs and MDSCs exert tissue repair and immunoregulatory function. Using mouse liver cancer, ConA induced hepatitis and allogenic collagen induced arthritis model, to investigate the location of BMSCs in a host and its regulation on MDSCs following its infusion into a mouse, and the influence of MDSCs in a host on the transplanted BMSCs. Make use of a inducement MDSCs activate and directional differentiation methods of BMSCs in vitro,the interaction of BMSCs and MDSCs and related mechanisms will be further investigated.Our research may clarify the important differentiation and final destination issues as BMSCs are transplaned into a host,which will provide key parameter for the following clinical application of BMSCs and scientific basis for a persistent progression of stem cell research and application.

揭示骨髓间充质干细胞(BMSCs)体内移植的分化、转归及其相关机制是当前BMSCs研究的关键。本项目是基于目前BMSCs在组织修复和免疫调节的理论研究基础，针对在机体发生感染或肿瘤时，骨髓中BMSCs与髓系来源抑制细胞(MDSCs)可以迅速动员并释放至外周组织及病灶中继而发挥组织修复和/或免疫调控功能这一现象，采用小鼠肝癌、刀豆蛋白A诱导急性肝炎和异种胶原蛋白诱导的关节炎模型，探讨BMSCs体内移植后在宿主体内的定位及其对宿主MDSCs的调控、MDSCs对体内移植的BMSCs的影响，并利用体外诱导MDSCs活化及BMSCs定向分化的方法，进一步揭示BMSCs与MDSCs之间的相互作用及相关机制。本研究可解决目前BMSCs体内移植的分化转归的关键问题，不仅能为今后BMSCs的临床应用提供关键参数，并且为干细胞研究和应用的可持续性发展提供相关科学依据。

骨髓间充质干细胞（BMSCs）与髓系抑制细胞（MDSCs）均来源于骨髓，在肿瘤等病理状态下从骨髓动员至外周发挥免疫调控作用并参与疾病的发生、发展等过程，但BMSCs与MDSCs是否相互作用尚不明确。本课题（1）首先采用小鼠肿瘤模型探讨BMSCs对MDSCs的调控作用。结果发现BMSCs可抑制小鼠外周血和骨髓中MDSCs生成，进而抑制小鼠黑色素瘤B16-F10肺转移形成并延长小鼠生存期。体外实验进一步证实BMSCs可以抑制MDSCs的生成。（2）对肺癌患者围手术期MDSCs变化及其功能的研究发现肺癌患者术后外周血MDSCs细胞较术前显著增高；外周血清MCP-1等趋化因子及促血管生成因子VEGF浓度较术前显著增高；裸鼠致瘤能力结果显示术后MDSCs促肿瘤血管生成和肿瘤生长能力较术前MDSCs增强。（3）采用小鼠自发肺转移模型，发现手术创伤可以诱导MDSCs并促肿瘤转移形成，且创伤的程度与肿瘤转移数量呈正相关；BMSCs可抑制手术后MDSCs生成进而预防手术后肿瘤转移形成。（4）通过检测肺癌患者围手术期外周血MDSCs和Treg的变化，发现手术后MDSCs和Treg较术前显著升高，且术后MDSCs和Treg呈正相关，体外实验证实术后MDSCs可诱导Treg生成，且MDSCs诱导Treg依赖细胞间相互接触。（5）最后采用小鼠博来霉素诱导肺损伤/肺纤维化模型，发现博来霉素诱导小鼠肺损伤早期骨髓动员Gr-1HighCD11b+细胞（粒细胞样MDSCs）通过IL-1等因子促肺损伤，BMSCs通过分泌M-CSF诱导Gr-1HighCD11b+细胞分化为具有免疫抑制作用Gr-1LowCD11b+细胞（单核细胞样MDSCs）从而减轻肺损伤。综合上述研究结果，本研究揭示了BMSCs对MDSCs的调控作用及其机制，为BMSCs的临床应用奠定了坚实的工作基础。项目资助发表SCI收录论著3篇，待发表1篇。培养博士研究生1名。项目投入经费48万元，支出48万元。