Research Center for Blood Engineering and Manufacturing, Cyrus Tang Medical Institute, Suzhou Medical College of Soochow University, Suzhou, China.
State Key Laboratory of Radiation Medicine and Protection, National Research Center for Hematological Diseases, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Aging Cell. 2023 Aug;22(8):e13889. doi: 10.1111/acel.13889. Epub 2023 May 24.
The bone marrow niche maintains hematopoietic stem cell (HSC) homeostasis and declines in function in the physiologically aging population and in patients with hematological malignancies. A fundamental question is now whether and how HSCs are able to renew or repair their niche. Here, we show that disabling HSCs based on disrupting autophagy accelerated niche aging in mice, whereas transplantation of young, but not aged or impaired, donor HSCs normalized niche cell populations and restored niche factors in host mice carrying an artificially harassed niche and in physiologically aged host mice, as well as in leukemia patients. Mechanistically, HSCs, identified using a donor lineage fluorescence-tracing system, transdifferentiate in an autophagy-dependent manner into functional niche cells in the host that include mesenchymal stromal cells and endothelial cells, previously regarded as "nonhematopoietic" sources. Our findings thus identify young donor HSCs as a primary parental source of the niche, thereby suggesting a clinical solution to revitalizing aged or damaged bone marrow hematopoietic niche.
骨髓龛维持造血干细胞（HSC）的体内平衡，其功能会随着生理衰老人群和血液恶性肿瘤患者的衰老而下降。目前的一个基本问题是，HSC 是否以及如何能够更新或修复其龛位。在这里，我们发现基于破坏自噬作用而使 HSC 失能会加速龛位衰老，而移植年轻的、而非年老的或受损的供体 HSC 可以使宿主携带人为受损龛位的小鼠和生理衰老的宿主小鼠以及白血病患者中的龛位细胞群体正常化，并恢复龛位因子。从机制上讲，使用供体谱系荧光示踪系统鉴定的 HSC 以自噬依赖性的方式在宿主中分化为功能性龛位细胞，包括间充质基质细胞和内皮细胞，这些细胞以前被认为是“非造血”来源。因此，我们的发现将年轻的供体 HSC 鉴定为龛位的主要亲本来源，从而为恢复衰老或受损的骨髓造血龛位提供了一种临床解决方案。
