Macrophage-derived amphiregulin induces myofibroblast transition in adipogenic lineage precursors near Staphylococcus aureus abscess in bone marrow

  • Nat Commun. 2025 Sep 25;16(1):8409. doi: 10.1038/s41467-025-63551-7.
Bingsheng Yang  #  1  2  3 ,  Jianwen Su  #  1  2 ,  Jichang Wu  #  1  2 ,  Zhongwen Wang  1  2 ,  Jin Hu  1  2 ,  Mankai Yang  1  2 ,  Yihuang Lin  1  2 ,  Mingchao Jin  1  2 ,  Xiaochun Bai  4 ,  Bin Yu  1  2 ,  Xianrong Zhang  5  6
Affiliations
  • 1. Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 2. Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 3. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 4. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 5. Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 6. Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 40998791 DOI: 10.1038/s41467-025-63551-7
Abstract

The formation of Staphylococcus aureus (S. aureus) abscesses is a well-established determinant of persistent skeletal infections, yet the mechanisms underlying Bacterial persistence remain elusive. Here, we demonstrate that bone marrow adiponectin-positive (Adipoq+) precursors are mobilized to surround S. aureus abscesses and undergo myofibroblast differentiation. This phenotypic transition induces vascular constriction, thereby impairing local perfusion and impeding effective Bacterial clearance. Mechanistically, macrophage-derived Amphiregulin (AREG) activates EGFR signaling on Adipoq+ cells, triggering the mTOR/YAP pathway to drive their myofibroblast transition. Importantly, genetic ablation of Adipoq+ cells, cell-specific deletion of the AREG/EGFR axis, or pharmacological inhibition of EGFR/mTOR signaling effectively alleviates fibrosis, restores vascular perfusion and Antibiotic delivery, and promotes Bacterial eradication from abscesses. Our findings implicate a macrophage-Adipoq+ cell regulatory axis that sustains S. aureus persistence in osteomyelitis and identify therapeutic targeting of this axis as a strategy to enhance Antibiotic efficacy against S. aureus skeletal infections.

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