Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing

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.

Neurological heterotopic ossification: novel mechanisms, prognostic biomarkers and prophylactic therapies

“…However, in a model of HO induced by burn and tenotomy, although injection of mice with clodronate-loaded liposomes decreased total HO volume by~50%, HO was still observed in all mice. 76 Although further studies are required, taken together these findings suggest that the contribution of resident tissue macrophages may differ between HO and NHO.…”

Underlying Ossification Phenotype in a Murine Model of Metastatic Synovial Sarcoma

“…The development of a boney matrix within the mature dermis initiates approximately 9-12 months post-hatch, when mesenchymal stem cells differentiate into osteoblasts to form qualitatively normal bone [30]. Most forms of HO are triggered and exacerbated by trauma, when faulty mechanisms of inflammation initiate the aberrant cell differentiation of mesenchymal stem cells involved in tissue regeneration during wound healing [31]. Consequently, a local osteogenic program is expressed and leads to the production of heterotopic bone in the affected tissue.…”

Mechanism of traumatic heterotopic ossification: In search of injury‐induced osteogenic factors

“…Under normal physiological conditions, circulating TGF-β1 acts to maintain the osteoblastic differentiation threshold to control aberrant osteogenesis, whereas under pathological conditions resulting from severe trauma, the level or activity of TGF-β1 is reduced or blunted, resulting in aberrant osteogenesis factor, and when its effects on the immune and other systems are also taken into consideration, its role can be pro-osteogenic. [79][80][81][82][83] We speculate that this is due to the different cellular pathways that lead to bone formation, namely endochondral ossification and intramembranous ossification. Endochondral ossification progresses through a cartilaginous precursor stage which requires TGF-β signalling for chondrogenesis, whereas in cases of intramembranous ossification, TGF-β signalling always exerts a direct inhibitory effect on stem cell osteogenesis.…”

“…87 Another study using a burn injury and Achilles tenotomy HO model confirms that clodronate liposome treatment specifically reduces local Ly6C low macrophage number; however, this time decreased HO volume has been found. 80 Thus far, no consensus has been reached regarding the relationship between macrophage phenotype and HO pathogenesis. However, it is generally agreed that macrophage heterogeneity exists and that change in macrophage phenotype is a key in the progression and regression of the HO lesion.…”