2. Academic Validation
  3. Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing

Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing

  • J Clin Invest. 2024 Nov 7;135(2):e180679. doi: 10.1172/JCI180679.
Ruiying Chen 1,  Xiaomeng Zhang 1,  Bin Li 2 3 4 5,  Maurizio S Tonetti 1,  Yijie Yang 1,  Yuan Li 1,  Beilei Liu 1,  Shujiao Qian 1,  Yingxin Gu 1,  Qingwen Wang 6 7,  Kairui Mao 8,  Hao Cheng 2 7 9,  Hongchang Lai 1,  Junyu Shi 1
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Implantology, Shanghai PerioImplant Innovation Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
  • 2 Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Thoracic Surgery of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Integrated TCM & Western Medicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 4 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
  • 5 Department of Oncology, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 6 Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Shenzhen, Guangdong, China.
  • 7 Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Guangdong, China.
  • 8 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 9 Center for Cancer Immunology Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
PMID: 39509336 DOI: 10.1172/JCI180679
Abstract

Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Tregs are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and a mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Tregs from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Tregs supported the accumulation and osteogenic differentiation of SSCs and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression levels of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Tregs, which bound to the Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg signaling to enhance bone repair and regeneration.

Keywords

Bone biology; Bone disease; Bone marrow.

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