The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells¹. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division^2,3,4. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)⁵, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.

大多数静止的造血干细胞 (HSC) 的激活是终生产生血细胞的先决条件¹。这个过程需要进行重大的分子改造，以允许 HSC 满足细胞分裂^2,3,4的调节和代谢要求。干细胞激活后控制细胞重编程以及随后干细胞恢复静止的机制尚未得到充分表征。在这里，我们展示伴侣介导的自噬 (CMA) ⁵，溶酶体蛋白降解的一种选择性形式，参与维持成年小鼠的 HSC 功能。CMA 是干细胞中蛋白质质量控​​制和 HSC 激活后脂肪酸代谢上调所必需的。我们发现 HSC 中的 CMA 活性随着年龄的增长而降低，并表明 CMA 的遗传或药理学激活可以恢复老年小鼠和人类 HSC 的功能。总之，我们的研究结果提供了 CMA 在维持质量控制、适当的能量学和整体长期 HSC 功能方面的作用的机制见解。我们的工作表明，CMA 可能是在衰老或干细胞移植等情况下增强 HSC 功能的有前途的治疗靶点。