TGFβ-SHP-1信号通路调控造血干细胞衰老的分子机制研究

Aged hematopoietic stem cells (HSCs) have impaired ability in hematopoiesis due to cell cycle activation and self-renewal defect. How to efficiently promote HSC activation and facilitate their self-renewal is critical for anti-aging and rejuvenate aged HSCs. The applicant found that TGFβ-SHP-1 pathway is critical for suppressing HSC cell cycle activation and limiting their self-renewal. Preliminary data also showed that TGFβ signaling is activated in aged bone marrow microenvironment. Therefore, in this proposal the applicant will investigate the role of TGFβ-SHP-1 pathway in HSC aging. We will investigate the transcription and epigenetic profile of HSCs during activation after blocking TGFβ-SHP-1 pathway and during aging. The success will help identify critical molecules that contribute to HSC activation and HSC aging which will be used as potential drug targets for stem cell anti-aging therapy.

衰老造血干细胞因细胞周期活化障碍而导致自我更新能力减弱和造血功能下降，因此有效激活衰老造血干细胞的细胞周期增加其自我更新能力是延缓和逆转血液系统衰老的关键。申请人前期工作中通过多种条件型基因敲除小鼠模型发现TGFβ-SHP-1信号通路对于抑制造血干细胞活化调控其自我更新能力有重要作用，同时发现衰老小鼠骨髓微环境中的TGFβ信号明显增加。这提示TGFβ-SHP-1信号新通路很可能参与了造血干细胞的衰老调控。因此，本课题将在此基础上深入研究TGFβ-SHP-1信号通路调控造血干细胞衰老的作用和机制，并将借助已建立的动物模型，进一步阐明造血干细胞活化的转录组和表观遗传组调控机制，借助高通量生物信息学分析结合体内、外功能实验，筛选TGFβ-SHP-1信号通路下游调控造血干细胞活化和衰老的关键信号分子，为治疗造血干细胞衰老提供理论依据和潜在的治疗靶点。

本项目研究了造血干细胞（HSC）自我更新调控和衰老的分子机制，研究解析了TGFβ-SHP-1通路维持HSC 自我更新、长期造血能力参与HSC衰老调控的关键机制，发现衰老过程中密质骨骨髓中的巨核-施旺细胞微环境发生损伤，导致密质骨HSC淋系分化能力降低且衰老程度明显高于松质骨HSC，本研究还发现导致密质骨HSC衰老的主要原因是该区域HSC存在更强的炎症反应和DNA损伤。这一发现对于改善衰老导致的血液系统的损伤具有重要的临床指导意义。