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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 L, 2020. "Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14172-4
    DOI: 10.1038/s41467-019-14172-4
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