Multimodal analyses of immune cells during bone repair identify macrophages as a therapeutic target in musculoskeletal trauma  

作　　者：Yasmine Hachemi Simon Perrin Maria Ethel Anais Julien Julia Vettese Blandine Geisler Christian Göritz Céline Colnot 

机构地区：[1]Univ Paris Est Creteil,INSERM,IMRB,Creteil,France [2]Department of Cell and Molecular Biology,Karolinska Institutet,Stockholm,Sweden [3]Center for Neuromusculoskeletal Restorative Medicine,Hong Kong Science Park,Shatin,Hong Kong,China

出　　处：《Bone Research》2024年第4期818-831,共14页骨研究(英文版)

基　　金：supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR072707 (C.C.and Ted Miclau)and R01 AR081671 (C.C.and Ralph Marcucio);Agence Nationale de la Recherche ANR-18-CE14-0033 and ANR-21-CE18-007-01 (C.C.)。

摘　　要：Musculoskeletal traumatic injuries(MTI)involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion.The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells(SSPCs)remains unknown.Here,we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory,pro-repair and anti-inflammatory profiles.Concurrently,SSPCs transition via a pro-and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation.In a preclinical MTI mouse model,the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation.Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion.Finally,pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing.These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.

关 键 词：SKELETAL HEALING TRAUMA 

分 类 号：R683[医药卫生—骨科学]