Restoring balanced HSC youth

Abstract

Hematopoietic stem cells (HSCs) in aged individuals become less functional in their regenerative potential and biased towards myeloid cell output with reduced lymphoid and erythroid cell production. In Nature Aging, Sun et al. investigate the cell-intrinsic mechanism that underlies skewed myelopoiesis in aged HSCs. Comparing transcriptional differences between HSCs from young and old mice, the authors identified candidate genes that were subsequently targeted by CRISPR-mediated mutagenesis in HSCs from old Cas9 mice. This screen identified Cd38 and Clu (encoding clusterin), with the latter shown to be a key driver of myeloid production bias in aged HSCs. Loss of clusterin led to more balanced lymphoid-myeloid cell output and increased long-term reconstitution potential. Mechanistically, cytosolic clusterin associates with mitochondria proteins TOM20 and MFN2, leading to increased mitochondrial hyperfusion as well as reduced mitophagy. Higher expression of Clu or Cd38 caused excessive mitochondrial oxidative phosphorylation and reactive oxygen species (ROS) production, increased DNA damage and activation of the p38 MAPK pathway in aged HSCs. The clusterin-dependent increase in mito-ROS and phosphorylated p-p38 increased the expression and activity of the transcription factor CEBPB, resulting in myeloid-biased lineage differentiation of aged HSC progeny cells.

Original reference: Nat. Aging https://doi.org/10.1038/s43587-025-00908-z (2025)