Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function

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.