Journal of Extracellular Vesicles (Apr 2024)
Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification
- Jianfei Yan,
- Bo Gao,
- Chenyu Wang,
- Weicheng Lu,
- Wenpin Qin,
- Xiaoxiao Han,
- Yingying Liu,
- Tao Li,
- Zhenxing Guo,
- Tao Ye,
- Qianqian Wan,
- Haoqing Xu,
- Junjun Kang,
- Naining Lu,
- Changhe Gao,
- Zixuan Qin,
- Chi Yang,
- Jisi Zheng,
- Pei Shen,
- Lina Niu,
- Weiguo Zou,
- Kai Jiao
Affiliations
- Jianfei Yan
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Bo Gao
- Institute of Orthopaedic Surgery Xijing Hospital, Fourth Military Medical University Xi'an Shaanxi China
- Chenyu Wang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China
- Weicheng Lu
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Wenpin Qin
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Xiaoxiao Han
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Yingying Liu
- Department of Neurobiology The Fourth Military Medical University Xi'an Shaanxi China
- Tao Li
- Center for Spintronics and Quantum Systems, State Key Laboratory for Mechanical Behavior of Materials, Department of Materials Science and Engineering Xi'an Jiaotong University Xi'an Shaanxi China
- Zhenxing Guo
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Tao Ye
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China
- Qianqian Wan
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China
- Haoqing Xu
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Junjun Kang
- Department of Neurobiology The Fourth Military Medical University Xi'an Shaanxi China
- Naining Lu
- Department of Neurobiology The Fourth Military Medical University Xi'an Shaanxi China
- Changhe Gao
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- Zixuan Qin
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China
- Chi Yang
- Department of Oral Surgery Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, and National Clinical Research Center of Stomatology Shanghai China
- Jisi Zheng
- Department of Oral Surgery Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, and National Clinical Research Center of Stomatology Shanghai China
- Pei Shen
- Department of Oral Surgery Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, and National Clinical Research Center of Stomatology Shanghai China
- Lina Niu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China
- Weiguo Zou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences, University of Chinese Academy of Sciences Shanghai China
- Kai Jiao
- Department of Stomatology Tangdu hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University Xi'an Shaanxi China
- DOI
- https://doi.org/10.1002/jev2.12425
- Journal volume & issue
-
Vol. 13,
no. 4
pp. n/a – n/a
Abstract
Abstract Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single‐cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV‐releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.
Keywords
- calcified apoptotic vesicles
- extracellular matrix
- heterotopic ossification
- macrophage polarization
- osteogenic microenvironment
