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

Michael Sorkin, Amanda K. Huber, Charles Hwang, William F. Carson, Rajasree Menon, John Li, Kaetlin Vasquez, Chase Pagani, Nicole Patel, Shuli Li, Noelle D. Visser, Yashar Niknafs, Shawn Loder, Melissa Scola, Dylan Nycz, Katherine Gallagher, Laurie K. McCauley, Jiajia Xu, Aaron W. James, Shailesh Agarwal, Stephen Kunkel, Yuji Mishina and Benjamin Levi ()
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Michael Sorkin: University of Michigan
Amanda K. Huber: University of Michigan
Charles Hwang: University of Michigan
William F. Carson: University of Michigan
Rajasree Menon: University of Michigan
John Li: University of Michigan
Kaetlin Vasquez: University of Michigan
Chase Pagani: University of Michigan
Nicole Patel: University of Michigan
Shuli Li: University of Michigan
Noelle D. Visser: University of Michigan
Yashar Niknafs: University of Michigan
Shawn Loder: University of Michigan
Melissa Scola: University of Michigan
Dylan Nycz: University of Michigan
Katherine Gallagher: University of Michigan
Laurie K. McCauley: University of Michigan
Jiajia Xu: Johns Hopkins University
Aaron W. James: Johns Hopkins University
Shailesh Agarwal: University of Michigan
Stephen Kunkel: University of Michigan
Yuji Mishina: University of Michigan
Benjamin Levi: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14172-4

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