Youthfulness of marrow Adipoq⁺ cells maintained by Cbfβ facilitates stem cell-based bone repair

Abstract

Exhaustion of skeletal stem and progenitor cells (SSPCs) drives age-related delays in fracture repair, yet the upstream regulators of SSPC maintenance are unclear. We identify that core-binding factor β (Cbfβ) in bone marrow Adipoq⁺ cells (BMACs) is essential for maintaining SSPC number and function. Cbfβ deletion in BMACs (CKO) leads to SSPC depletion, including periosteal populations, and impairs bicortical fracture healing in mice. Multi-omics (RNA-seq, CUT&Tag-seq, and ATAC-seq) reveal that Cbfβ preserves chromatin accessibility at DNA repair loci, maintaining genomic stability, preventing BMAC senescence, and mitigating the senescence-associated secretory phenotype (SASP). Senolytic therapy alleviates BMAC senescence, restores SSPC populations, and improves bone repair in CKO mice. In both humans and mice, Cbfβ expression declines with aging, accompanied by increased BMAC senescence. AAV-mediated Cbfβ overexpression restores aging-related bone repair and SSPC decline. These findings reveal a novel mechanism in which Cbfβ in BMACs regulates SSPC maintenance via a senescence/SASP axis, offering a potential therapeutic strategy for age-related bone repair deficits.

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Funding

The Key Project of Zhejiang Provincial Medical and Health Science and Technology Plan WKJ-ZJ-2443

National Natural Science Foundation of China (National Science Foundation of China)(82001461)

Application Program for Chinese Manned Space Station YYWT-0901-EXP-06; NSM0617

National Key Research and Development Program of China 2023YFC2509200 Zhejiang Science Foundation for Distinguished Young Scholars LR24H140001

Zhejiang Provincial “Ten Thousand Plan” Outstanding Young Scholar National Key Research and Development Program of China 2023YFA1800602 The Key Program of the Zhejiang Provincial Natural Science Foundation of China under the Huadong Medicine Joint Fund LHDM25H280002 Application Program for Chinese Manned Space Station CMSS-2024-1-A-019

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