Aging of the blood system is characterized by increased hematopoietic stem cells (HSCs) and myeloid-biased differentiation leading to a higher propensity for hemato-logical malignancies. Unraveling cell-intrinsic mechanisms regulating HSC aging could aid reversal or slowing of aging. We show that Asrij depletion results in loss of organelle homeostasis and premature HSC aging. Pharmacological correction of mitochondrial and proteasome activity in asrij KO mice restored HSC and myeloid cell frequencies. Furthermore, lysophosphatidic acid-induced Asrij upregulation in aged WT mice rescued mitochondrial and proteasome activity and restored HSC frequency. Our results highlight a new role for Asrij in preventing HSC aging by regulating organelle homeostasis and will help decipher organelle dynamics in HSC longevity.
Link to full article: https://onlinelibrary.wiley.com/doi/10.1111/acel.13570
We provide the first report that HSC aging is associated with Asrij-dependent simultaneous dysfunction in mitochondrial, endosomal, and proteasomal machineries. We demonstrate that restoring organelle homeostasis by pharmacological intervention can maintain HSC stemness and lineage choice, thereby reversing phenotypes of premature aging in young asrij KO HSCs. We propose that Asrij is a critical node in organelle control of HSC aging.
© 2021, JNCASR, Jakkur, Bangalore, India