Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun. 2020 Feb 5;11(1):722. doi: 10.1038/s41467-019-14172-4.
Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
异位骨化（HO）是一种异常的再生过程，在肌肉骨骼创伤后会诱导异位骨形成，其中间充质干细胞（MSC）分化为成骨软骨细胞，而不是成肌细胞或腱细胞。尽管经常发生肌肉骨骼创伤住院治疗，但调节随后的伤口愈合和组织再生的炎症反应和细胞群体动态仍不清楚。在这里，我们使用创伤诱导的 HO 小鼠模型，研究了初始损伤后炎症反应的局部微环境。单细胞转录组分析在损伤部位鉴定出不同的单核细胞/巨噬细胞群体，使用轨迹分析阐明了它们随时间的动态变化。从机制上讲，产生转化生长因子β-1（TGFβ1）的单核细胞/巨噬细胞与 HO 和异常的软骨祖细胞分化有关，而 CD47 激活肽可降低系统巨噬细胞 TGFβ 水平并有助于改善 HO。因此，我们的数据表明 CD47 激活可作为一种治疗方法，用于调节单核细胞/巨噬细胞表型、MSC 分化和伤口愈合过程中的 HO 形成。
