Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing
Ruiying Chen, … , Hongchang Lai, Junyu Shi
Ruiying Chen, … , Hongchang Lai, Junyu Shi
Published November 7, 2024
Citation Information: J Clin Invest. 2025;135(2):e180679. https://doi.org/10.1172/JCI180679.
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Research Article Bone biology

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

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.

Authors

Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi

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Figure 1

Treg accumulation in injured bone tissue enables bone repair.

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Treg accumulation in injured bone tissue enables bone repair. (A) Repres...
(A) Representative images of colocalization of CD4 (red) and FOXP3-GFP (green) in uninjured/injured bone tissue on day 0 (uninjury), day 3, day 7, day 14, and day 28 after operation. Scale bars: 100 μm (left); 10 μm (right). (B) Representative flow cytometry analysis of Tregs from callus tissue on day 0 (uninjury), day 3, day 7, day 14, and day 28 after operation. The numbers indicate the proportion of Tregs in the frame. (C) The proportions of Tregs among CD4+TCRβ+ cells, the numbers of Tregs, and the proportions of CD4+ cells at indicated time points in bone callus tissue (blue) and in SP (red). n = 4–5 per group. (D) Diagram illustration of Treg depletion by DT injection after bone-defect surgery. (E) Representative flow cytometry graphs of Treg proportions in control group (Cntrl) and Treg-depletion group. The numbers indicate the proportion of Tregs in the frame. (F) The proportions of Tregs among CD4+TCRβ+ cells. n = 5 per group. (G) Safranin O staining of injured bone tissues from the control group and Treg-depletion group. Scale bars: 200 μm. (H) The Safranin O images were analyzed using Image J, version 1.48. n = 4 per group. (I) H&E staining of injured bone tissues from the control group and Treg-depletion group. Scale bars: 200 μm. All data are represented as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.005; ****P ≤ 0.001, as determined by unpaired 2-tailed Student’s t test (F and H) or 1-way ANOVA with Bonferroni’s multiple-comparisons test (C).