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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 [1], to the maintenance and function of hematopoietic stem cells (HSCs) [2]. Various stressors upregulate chaperone-mediated autophagy [1]; however, various studies have linked aging [1, 3, 4] and both metabolic [5] and neurodegenerative [5] disorders with a decline in activity. Importantly, HSCs also display a reduced capacity for self-renewal [6] 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 [2].

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 [9] 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!


References

  1. Kaushik S and Cuervo AM, The coming of age of chaperone-mediated autophagy. Nature Reviews Molecular Cell Biology 2018;19:365-381.
  2. Dong S, Wang Q, Kao Y-R, et al., Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature 2021;591:117-123.
  3. Valdor R, Mocholi E, Botbol Y, et al., Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. Nature Immunology 2014;15:1046-1054.
  4. Cuervo AM and Dice JF, Age-related Decline in Chaperone-mediated Autophagy *. Journal of Biological Chemistry 2000;275:31505-31513.
  5. Sooparb S, Price SR, Shaoguang J, et al., Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus. Kidney International 2004;65:2135-2144.
  6. Dykstra B, Olthof S, Schreuder J, et al., Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. Journal of Experimental Medicine 2011;208:2691-2703.
  7. Sudo K, Ema H, Morita Y, et al., Age-Associated Characteristics of Murine Hematopoietic Stem Cells. Journal of Experimental Medicine 2000;192:1273-1280.
  8. 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.
  9. 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.