骨髓间充质细胞(BM-MSC)的低免疫原性和免疫调节作用，已被应用于移植物抗宿主病的治疗。但是，近来研究认为，一部分MSC具有免疫激活和炎症刺激作用，与MSC的TLR4激活有关。我们发现，TLR4激活可使BM-MSC中淋巴细胞活化因子的表达增强；而活化的T淋巴细胞可诱导BM-MSC脂肪化，使其成骨成脂分化失衡，进而削弱MSC的造血支持能力，是免疫相关造血衰竭的重要致病因子。由此我们推测，TLR4及下游信号参与了细胞免疫紊乱时BM-MSC的脂肪化进程，是免疫相关造血衰竭骨髓微环境恶化的重要因素。本课题拟以TLR4-/-的基因缺陷小鼠为载体，研究细胞免疫紊乱背景下TLR4信号通路对BM-MSC成脂成骨分化的影响，并以在体可视技术在活体小鼠中连续、动态观察浸润至骨髓内的淋巴细胞与各种造血成分相互作用的时间-空间效应。研究免疫相关造血衰竭的发生机制，对探索该类疾病免疫治疗的新靶点具有重要意义。

Based on the low immunogenicity and immune modulatory function, bone marrow mesenchymal stroma cells (BM-MSCs) have been applied to treat graft-versus-host diseases. However, recent studies indicated that MSCs were able to exert immune-stimulating effect after Toll-like receptor 4 (TLR4) on their surface was stimulated. We previously reported that activation of TLR4 pathway increased expression of B cell activating factor in BM-MSCs. We also found that T lymphocyte was a major pathogen resulting in deterioration of bone marrow microenvironment during the occurrence of immune-related BM failure. Activation of T lymphocytes was able to induce BM-MSC adipogenic differentiation and to reduce their hematopoietic supportive function. However, in immune-related BM failure, the role of TLR4 signaling pathway in MSCs' over-adipogenesis remains largely unknown. In this study, we will use TLR4-/- mice to generate immune-related BM failure model, and to investigate the regulating mechanism of TLR4 during the process of BM-MSC adipocytic differentiation in cellular immune abnormity. In addition, the spatio-temporal relationship between infiltrated T cell and hematopoietic component in bone marrow will be detected by in vivo image techniques. The result of this study will clarify the pathogenic mechanism of bone marrow-restricted immune disorders and thus help to explore the new therapeutic target for immune-related BM failure.