Chaperone-mediated autophagy sustains haematopoietic stem-cell function

• Published in: Nature (London) Vol. 591; no. 7848; pp. 117 - 123
• Main Authors: Dong, Shuxian, Wang, Qian, Kao, Yun-Ruei, Diaz, Antonio, Tasset, Inmaculada, Kaushik, Susmita, Thiruthuvanathan, Victor, Zintiridou, Aliona, Nieves, Edward, Dzieciatkowska, Monika, Reisz, Julie A., Gavathiotis, Evripidis, D’Alessandro, Angelo, Will, Britta, Cuervo, Ana Maria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2021; Nature Publishing Group
• Subjects: 13; 13/100; 13/31; 14; 14/35; 631/136/532/1542; 631/136/7; 631/80/39/2345; 64/60; 82; 82/58; 82/80; Adaptation; Adult; Age; Aged; Aging; Animals; Autophagy; Biodegradation; Blood; Bone marrow; Cell activation; Cell cycle; Cell Self Renewal; Cells, Cultured; Chaperone-Mediated Autophagy - drug effects; Chaperone-Mediated Autophagy - genetics; Chaperone-Mediated Autophagy - physiology; Energy Metabolism; Fatty acids; Female; Glycolysis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Humanities and Social Sciences; Humans; Linoleic Acid - metabolism; Lysosomal protein; Male; Metabolism; Mice; Middle Aged; multidisciplinary; Multiple Myeloma - pathology; Phagocytosis; Proteins; Quality control; Rejuvenation; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Transplantation; Young Adult
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-03129-z

The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells 1 . This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division 2 – 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. Haematopoietic stem cells show progressive functional decline with age that can be reversed by stimulation of chaperone-mediated autophagy in old mice and aged humans.