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

Ninghe Sun; Chun-Hsin Lin; Michelle Y Li; Yuting Wang; Danyang Chen; Xiangle Ren; Feng Zhang; Yi Zhang

doi:10.1038/s43587-025-00908-z

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

Nat Aging. 2025 Jun 30. doi: 10.1038/s43587-025-00908-z. Online ahead of print.

Authors

Ninghe Sun^{1

2

3}, Chun-Hsin Lin^{1

2

3}, Michelle Y Li^{1

2

3}, Yuting Wang^{1

2

3}, Danyang Chen⁴, Xiangle Ren^{1

2

3}, Feng Zhang⁵, Yi Zhang^{6

7

8

9

10}

Affiliations

¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
² Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
³ Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
⁴ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
⁵ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁶ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
⁷ Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
⁸ Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
⁹ Department of Genetics, Harvard Medical School, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
¹⁰ Harvard Stem Cell Institute, Boston, MA, USA. yzhang@genetics.med.harvard.edu.

PMID: 40588652
DOI: 10.1038/s43587-025-00908-z

Abstract

Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.