干细胞
造血
细胞生物学
自噬
下调和上调
生物
移植
生物化学
基因
医学
外科
细胞凋亡
作者
Shuxian Dong,Qian Wang,Yun Ruei Kao,Antonio Díaz,Inmaculada Tasset,Susmita Kaushik,Victor Thiruthuvanathan,Aliona Zintiridou,Edward Nieves,Monika Dzieciątkowska,Julie A. Reisz,Evripidis Gavathiotis,Angelo D’Alessandro,Britta Will,Ana María Cuervo
出处
期刊:Nature
[Springer Nature]
日期:2021-01-13
卷期号:591 (7848): 117-123
被引量:131
标识
DOI:10.1038/s41586-020-03129-z
摘要
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 division2-4. 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.
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