Chaperone-mediated autophagy sustains haematopoietic stem-cell function
Authors: Monika Dzieciatkowska
Edward Nieves
Angelo D&#x27;Alessandro
Yun-Ruei Kao
Aliona Zintiridou
Shuxian Dong
Ana Maria Cuervo
Qian Wang
Britta Will
Evripidis Gavathiotis
Julie A Reisz
Susmita Kaushik
Victor Thiruthuvanathan
Antonio Diaz
Inmaculada Tasset
Journal: Nature (2021)
Discipline: Multidisciplinary
Keywords: haematopoietic stem cells; HSC activation; chaperone-mediated autophagy; protein quality control; fatty acid metabolism
Affiliations: Department of Development and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA., Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY, USA., Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA., Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA., Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA., Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY, USA., Ruth L. and David S. Gottesman Institute for Stem Cell Biology, Albert Einstein College of Medicine, New York, NY, USA., Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY, USA. ., Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA. ., Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, NY, USA. ., Ruth L. and David S. Gottesman Institute for Stem Cell Biology, Albert Einstein College of Medicine, New York, NY, USA. ., Department of Development and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 An image in Extended Figure 8 seems to appear twice. Could the authors check to confirm that this is deliberate? Apologies if I am misunderstanding. ***  , 
 Dear Actinopolyspora Biskrensis: Thank you very much for the service that you and dedicate people like you provide to the scientific community by carefully reviewing published studies. Considering the extensive amount of data required now for publication, we all fear when assembling multi-panel images making some unintentional mistake. However, in this case the duplication of image is intentional and you may also note that the cells in the top insert in panel h are also shown in the top and bottom left insert of panel f and the full field of f and h (left) are the same. This duplication was intentional as we wanted to illustrate two different but related concepts here: 1) there is heterogeneity in the intensity of the CMA reporter (panel f) among different cell types and 2) those cells with higher fluorescence intensity (in f) are those showing less puncta (in h) and those with less fluorescence intensity (in f) are those showing more puncta (in h). In retrospective we should have improved the labeling and keep the same order (low puncta on top and high puncta at the bottom) to make the comparison easier. We apologize if this has created confusion, but want to reiterate that this was intentional to convey the two points indicated above. Best, Ana Maria , 
 #2 Thank you for responding and confirming. Best wishes. ,