Wang Jing, Zhang Linlin, Cui Xinyu, Xu Xiang, Guo Rui, Li Kairui, Zhang Li, Xu Bing, Jiang Cizhong, Yu Yong
Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Department of Hematology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Sci Immunol. 2025 Apr 11;10(106):eadr2041. doi: 10.1126/sciimmunol.adr2041.
Preserving hematopoietic stem cell (HSC) functionality is essential for maintaining healthy blood and the immune system throughout life. HSC function declines with age; however, the underlying mechanisms are not fully understood. Using an inducible mosaic mouse model to overexpress the transcription factor Bcl11a in the hematopoietic compartment, we found that an aging-related increase in Bcl11a mitigated HSC functional decline, promoted IL-1β production in the bone marrow (BM), and accelerated HSC attrition in a non-cell-autonomous manner. Aging-related inflammation in the BM enhanced Bcl11a and Fc receptor (FcR) expression in HSCs, and FcR signaling induced HSC differentiation. This was counteracted by Bcl11a through repression of . Bcl11a up-regulation promoted IL-1β production in BM myeloid cells, driving inflammation and HSC deterioration. Deletion of , or blocking IL-1β signaling, eliminated this non-cell-autonomous effect on HSC decline. These findings demonstrate that Bcl11a plays a dual role in HSCs during aging not only by cell-intrinsically preserving HSC function but also by promoting BM inflammation and HSC dysfunction.
维持造血干细胞（HSC）的功能对于终身维持健康的血液和免疫系统至关重要。HSC功能会随着年龄增长而下降；然而，其潜在机制尚未完全明确。利用一种可诱导的嵌合小鼠模型在造血区室中过表达转录因子Bcl11a，我们发现，与衰老相关的Bcl11a增加减轻了HSC功能衰退，促进了骨髓（BM）中白细胞介素-1β（IL-1β）的产生，并以非细胞自主方式加速了HSC损耗。BM中与衰老相关的炎症增强了HSC中Bcl11a和Fc受体（FcR）的表达，并且FcR信号传导诱导了HSC分化。这被Bcl11a通过对……的抑制所抵消。Bcl11a上调促进了BM髓样细胞中IL-1β的产生，驱动炎症和HSC恶化。删除……或阻断IL-1β信号传导消除了这种对HSC衰退的非细胞自主效应。这些发现表明，Bcl11a在衰老过程中在HSC中发挥双重作用，不仅通过细胞内在机制维持HSC功能，还通过促进BM炎症和HSC功能障碍。
