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Updated: Sep 17, 2025

Improving the Accuracy of Flow Cytometric Assessment of Mitochondrial Membrane Potential in Hematopoietic Stem and Progenitor Cells Through the Inhibition of Efflux Pumps
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Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function

Ninghe Sun1,2,3, Chun-Hsin Lin1,2,3, Michelle Y Li1,2,3

  • 1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.

Nature Aging
|June 30, 2025
PubMed

Insights

Aging impairs hematopoietic stem cells (HSCs). Clusterin (Clu) drives myeloid bias by affecting mitochondria. Depleting Clu rejuvenates HSC function and improves immunity.

Area of Science:

  • Hematology
  • Immunology
  • Aging Research
  • Molecular Biology

Background:

  • Aged hematopoietic stem cells (HSCs) show reduced self-renewal and skewed myeloid differentiation, impacting hematopoiesis and immunity.
  • The molecular mechanisms behind impaired aged HSC function are not fully understood.

Purpose of the Study:

  • To identify molecular regulators of impaired aged HSC function.
  • To elucidate the mechanism by which clusterin (Clu) drives myeloid-biased differentiation in aged HSCs.

Main Methods:

  • Conducted an in vivo CRISPR-Cas9 screen to identify genes regulating HSC differentiation.
  • Utilized molecular assays to investigate the interaction of Clu with Mfn2 and its effects on mitochondrial function and signaling pathways.
  • Performed transplantation studies using Clu-depleted aged HSCs.

Main Results:

  • Clusterin (Clu) was identified as a key driver of myeloid-biased differentiation in aged HSCs.
  • Clu upregulation in aged HSCs promotes mitochondrial hyperfusion via Mfn2 interaction.
  • Ablation of Clu reversed myeloid bias by attenuating oxidative phosphorylation and improving mitophagy through the OXPHOS-p38-Cebpb axis.

Conclusions:

  • Clusterin (Clu) is a critical regulator of aging-associated myeloid bias in HSCs.
  • The Mfn2-OXPHOS-p38-Cebpb axis mediates Clu's effect on myeloid differentiation.
  • Targeting Clu offers a potential strategy for rejuvenating aged hematopoietic and immune systems.

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