Abstract
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.
Highlights
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
Monocytes and macrophages are a heterogeneous population of cells comprised of functionally distinct subpopulations and their accurate identification has been hampered by a lack of sensitive biological tools
We identify cytokines that are expressed in the initial phase of the inflammatory response and characterize the inflammatory cells recruited in a model of musculoskeletal trauma leading to aberrant regeneration
Summary
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. An inflammatory response is mounted at the site of injury that promotes wound healing and regeneration of involved musculoskeletal tissues. Severe trauma can lead to aberrant wound healing through mechanisms of dysregulated inflammation resulting in fibrosis or stem cell differentiation into a tissue distinct from its original fate, such as heterotopic ossification (HO), which commonly occurs after severe burn or trauma[3]. While monocytes/ macrophages have been shown to play a role in aberrant wound healing,[9,10,11] the phenotypic and functional heterogeneity of this cell population in musculoskeletal trauma remain poorly understood. We investigate the inflammatory response occurring at the site of musculoskeletal extremity trauma leading to aberrant cell fate causing HO. Our findings propose a paradigm to understanding the functional impact of macrophages on MSC fate
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