You are hereJune 7, 2021 | Haematopoetic Stem Cells
Chaperone-mediated Autophagy Takes the Stress off HSCs
Review of “Chaperone-mediated autophagy sustains haematopoietic stem-cell function” from Nature by Stuart P. Atkinson
A recent study from researchers led by Britta Will and Ana Maria Cuervo (Albert Einstein College of Medicine, New York, NY, USA) explored the relevance of chaperone-mediated autophagy, a selective form of lysosomal protein degradation , to the maintenance and function of hematopoietic stem cells (HSCs) . Various stressors upregulate chaperone-mediated autophagy ; however, various studies have linked aging [1, 3, 4] and both metabolic  and neurodegenerative  disorders with a decline in activity. Importantly, HSCs also display a reduced capacity for self-renewal  and multi-lineage repopulation [7, 8] with age due, in part, to an extended exposure to a range of stressors. Now, Dong et al. report that targeting chaperone-mediated autophagy may represent an exciting means to enhance HSC function during the normal aging process or after stem cell transplantation by improving responses to stress by maintaining protein quality .
Using mice expressing a chaperone-mediated autophagy reporter construct, the authors discovered that quiescent HSCs from young mice showed higher basal activity, which became further upregulated in HSCs activated by exposure to a myeloablative agent. Additionally, analysis in older mice confirmed an age-associated reduction in chaperone-mediated autophagy in HSCs.
The study next selectively eliminated chaperone-mediated autophagy in hematopoietic cells, which revealed how this protein quality mechanism failed to affect multi-lineage blood cell differentiation in young mice but did support the functionality of HSCs under steady-state conditions and prevent HSC depletion after activation by maintaining protein quality and supporting a youthful metabolic profile. The authors next established that activated chaperone-mediated autophagy also supported the functionality of aged HSCs by maintaining youthful metabolic/proteostatic profile, while the restoration of chaperone-mediated autophagy through the oral administration of a pharmacological activator  prompted the rejuvenation of aged mouse HSCs by maintaining protein quality. Furthermore, the treatment of CD34+ human hematopoietic stem and progenitor cells from old donors with the chaperone-mediated autophagy activator markedly increased multi-lineage potency and supported long-term culture.
Overall, the authors confirm the need for adequate stress responses and protein quality control for the maintenance and function of HSCs and highlight the pharmacological activation of chaperone-mediated autophagy as an effective means of improving and restoring aged HSC function.
For more on how proper protein control through chaperone-mediated autophagy takes the stress off HSCs, stay tuned to the Stem Cells Portal!
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- Dong S, Wang Q, Kao Y-R, et al., Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature 2021;591:117-123.
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- Beerman I, Bhattacharya D, Zandi S, et al., Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proceedings of the National Academy of Sciences 2010;107:5465.
- Anguiano J, Garner TP, Mahalingam M, et al., Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nature Chemical Biology 2013;9:374-382.