Fujii Takayuki, Wada Susumu, Carballo Camila B, Bell Richard D, Morita Wataru, Nakagawa Yusuke, Liu Yake, Chen Daoyun, Pannellini Tania, Sokhi Upneet K, Deng Xiang-Hua, Park-Min Kyung Hyung, Rodeo Scott A, Ivashkiv Lionel B
Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center Hospital for Special Surgery New York NY USA.
Orthopaedic Soft Tissue Research Program Hospital for Special Surgery New York NY USA.
JBMR Plus. 2022 May 31;6(7):e10635. doi: 10.1002/jbm4.10635. eCollection 2022 Jul.
Macrophages are important for repair of injured tissues, but their role in healing after surgical repair of musculoskeletal tissues is not well understood. We used single-cell RNA sequencing (RNA-seq), flow cytometry, and transcriptomics to characterize functional phenotypes of macrophages in a mouse anterior cruciate ligament reconstruction (ACLR) model that involves bone injury followed by a healing phase of bone and fibrovascular interface tissue formation that results in bone-to-tendon attachment. We identified a novel "surgery-induced" highly inflammatory CD9+ IL1+ macrophage population that expresses neutrophil-related genes, peaks 1 day after surgery, and slowly resolves while transitioning to a more homeostatic phenotype. In contrast, CX3CR1+ CCR2+ macrophages accumulated more slowly and unexpectedly expressed an interferon signature, which can suppress bone formation. Deletion of resulted in an increased amount of bone in the surgical bone tunnel at the tendon interface, suggestive of improved healing. The "surgery-induced macrophages" identify a new cell type in the early phase of inflammation related to bone injury, which in other tissues is dominated by blood-derived neutrophils. The complex patterns of macrophage and inflammatory pathway activation after ACLR set the stage for developing therapeutic strategies to target specific cell populations and inflammatory pathways to improve surgical outcomes. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
巨噬细胞对损伤组织的修复很重要，但其在肌肉骨骼组织手术修复后的愈合过程中的作用尚未得到充分了解。我们使用单细胞RNA测序（RNA-seq）、流式细胞术和转录组学来表征小鼠前交叉韧带重建（ACLR）模型中巨噬细胞的功能表型，该模型涉及骨损伤，随后是骨和纤维血管界面组织形成的愈合阶段，最终形成骨与肌腱的附着。我们鉴定出一种新型的“手术诱导”的高炎症性CD9 + IL1 +巨噬细胞群体，其表达与中性粒细胞相关的基因，在手术后1天达到峰值，并在向更稳态表型转变时缓慢消退。相比之下，CX3CR1 + CCR2 +巨噬细胞积累得更慢，并且意外地表达了一种干扰素特征，该特征可抑制骨形成。缺失该特征导致肌腱界面手术骨隧道中的骨量增加，提示愈合得到改善。“手术诱导的巨噬细胞”在与骨损伤相关的炎症早期阶段鉴定出一种新的细胞类型，在其他组织中该阶段主要由血液来源的中性粒细胞主导。ACLR后巨噬细胞和炎症途径激活的复杂模式为开发针对特定细胞群体和炎症途径的治疗策略以改善手术结果奠定了基础。© 2022作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
