Tsc1-mTORC1信号作用于骨髓巨噬细胞对正常和移植造血干细胞的调控作用

Macrophage is an important component of the hematopoietic microenvironment, which can regulate the self-renewal, mobilization and apoptosis of hematopoietic stem cells (HSC) in a direct or indirect way. But the molecular mechanism is unknown. In our previous work, we found that the proportion of bone marrow HSC and the number of mature cells in peripheral blood increased in mice deficient of the mTORC1 inhibitor Tsc1. And we have found that Tsc1 can control the survival of peritoneal macrophages, phagocytosis, M1/M2 cytokine secretion, ROS production, which may also been altered in bone marrow macrophages and have important impacts on the HSC. Therefore, we hypothesized that Tsc1 may play an important role in the regulation of HSC homeostasis and function through the role of bone marrow macrophages. Our project attempts to investigate how Tsc1 acts on macrophages to regulate homeostasis and function of normal and transplanted HSC. Expected results will provide a theoretical basis for the pathogenesis and treatment of HSC and microenvironment related diseases.

骨髓巨噬细胞是造血微环境的重要组成部分，其可以通过直接或间接的方式调控造血干细胞（HSC）的自我更新、动员和凋亡。但是相关的分子机制未明。我们的前期工作发现巨噬细胞缺失mTORC1的抑制分子Tsc1时，骨髓HSC比例升高，外周血多种成熟细胞的数量增加。而我们已发现Tsc1可控制腹腔巨噬细胞的存活、吞噬、M1/M2细胞因子分泌、ROS产生，在骨髓中这些因素可能对HSC有重要影响。因此我们推测，Tsc1可能通过作用于骨髓巨噬细胞，对HSC自稳和功能发挥重要的调控作用。本课题拟研究Tsc1如何通过作用于骨髓巨噬细胞对正常HSC的自稳和功能发挥重要调控作用，解析其精确分子调控机制，并进一步探讨该通路如何调控移植HSC的存活与功能。我们的研究结果将为HSC和微环境相关疾病发病机理的阐明和治疗提供理论依据。

Tsc1作为重要的能量代谢调控分子，对于调控巨噬细胞和树突状细胞的生存，活化以及效应功能意义重大。课题通过建立树突状细胞（DC）谱系限定性Tsc1基因敲除小鼠，发现Tsc1敲除导致DC存活、抗原呈递等功能异常，且显著影响小鼠体内初始T细胞的静息状态；进一步通过探索Tsc1上游分子Lkb1的生理功能，课题首次揭示Lkb1对于Treg细胞的谱系稳定性的关键调控作用，而在DC中，Lkb1又以负反馈调节方式控制了Treg细胞数量。课题首次揭示了静息分子Tsc1和Lkb1通过多种方式调控免疫耐受的重要生理功能，为自身免疫疾病以及恶性肿瘤的治疗提供了潜在靶点。另外，我们与临床合作探究白血病的复发机制。