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

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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.

Abstract

Aberrant tissue repair may result in heterotopic ossification (HO), but how this process is regulated by local inflammatory responses is still unclear. Here the authors show, using a mouse burn/trauma model, that TGFβ-producing monocytes/macrophages at the injury site contribute to HO induction, while CD47 activation helps antagonize this process.

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Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Sarah Dick, Jill Macklin, Sara Nejat … (2018)

Macrophages promote both injury and repair following myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2− resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4−LYVE1−MHC-IIhiCCR2− macrophages and fully replaced TIMD4−LYVE1−MHC-IIhiCCR2+ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4− resident macrophage abundance within infarcted tissue while recruited, CCR2+ monocyte-derived macrophages adopted multiple cell fates, including those nearly indistinguishable from resident macrophages. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, highlighting a non-redundant, cardioprotective role of resident cardiac macrophages. Lastly, we demonstrate the ability of TIMD4 to be used as a durable lineage marker of a subset of resident cardiac macrophages.

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Colony-stimulating factor-1 in immunity and inflammation.

Violeta Chitu, E Richard Stanley (2006)

Colony-stimulating factor-1 (CSF-1, also known as macrophage-CSF) is the primary regulator of the survival, proliferation, differentiation and function of mononuclear phagocytes. Studies that involve CSF-1-deficient mice demonstrate that there is a variable requirement for CSF-1 in the development of individual mononuclear phagocyte populations. However, these cells uniformly express the CSF-1 receptor, and their morphology, phagocytosis and responsiveness to infectious and non-infectious stimuli is regulated by CSF-1. CSF-1 plays important roles in innate immunity, cancer and inflammatory diseases, including systemic lupus erythematosus, arthritis, atherosclerosis and obesity. In several conditions, activation of macrophages involves a CSF-1 autocrine loop. In addition, secreted and cell-surface isoforms of CSF-1 can have differential effects in inflammation and immunity.

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Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice.

Alexander V. Misharin, Carla M Cuda, Rana Saber … (2014)

Different subsets and/or polarized phenotypes of monocytes and macrophages may play distinct roles during the development and resolution of inflammation. Here, we demonstrate in a murine model of rheumatoid arthritis that nonclassical Ly6C(-) monocytes are required for the initiation and progression of sterile joint inflammation. Moreover, nonclassical Ly6C(-) monocytes differentiate into inflammatory macrophages (M1), which drive disease pathogenesis and display plasticity during the resolution phase. During the development of arthritis, these cells polarize toward an alternatively activated phenotype (M2), promoting the resolution of joint inflammation. The influx of Ly6C(-) monocytes and their subsequent classical and then alternative activation occurs without changes in synovial tissue-resident macrophages, which express markers of M2 polarization throughout the course of the arthritis and attenuate joint inflammation during the initiation phase. These data suggest that circulating Ly6C(-) monocytes recruited to the joint upon injury orchestrate the development and resolution of autoimmune joint inflammation.

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Author and article information

Contributors

Benjamin Levi: blevi@umich.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 5 February 2020

Publication date PMC-release: 5 February 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 722

Affiliations

[1 ]ISNI 0000000086837370, GRID grid.214458.e, Section of Plastic Surgery, Department of Surgery, , University of Michigan, ; Ann Arbor, MI 48109 USA

[2 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Pathology, , University of Michigan, ; Ann Arbor, MI 48109 USA

[3 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Computational Medicine and Bioinformatics, , University of Michigan, ; Ann Arbor, MI 48109 USA

[4 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Vascular Surgery, Department of Surgery, , University of Michigan, ; Ann Arbor, MI 48109 USA

[5 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Periodontics and Oral Medicine, , University of Michigan, ; Ann Arbor, MI 48109 USA

[6 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Pathology, , Johns Hopkins University, ; Baltimore, MD 21205 USA

[7 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Biologic and Material Sciences, School of Dentistry, , University of Michigan, ; Ann Arbor, MI 48109 USA

Author information

Aaron W. James http://orcid.org/0000-0002-2002-622X

Yuji Mishina http://orcid.org/0000-0002-6268-4204

Article

Publisher ID: 14172

DOI: 10.1038/s41467-019-14172-4

PMC ID: 7002453

PubMed ID: 32024825

SO-VID: af33d42c-c5af-4a48-a09a-81842302648d

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 February 2019

Date accepted : 13 December 2019

Funding

Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);

Award ID: K08GM109105

Award ID: R01GM123069

Award Recipient : Benjamin Levi

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)

Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);

Award ID: R01AR071379

Award Recipient : Benjamin Levi

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ScienceOpen disciplines: Uncategorized

Keywords: transforming growth factor beta,inflammation,osteoimmunology,systems analysis

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ScienceOpen disciplines: Uncategorized

Keywords: transforming growth factor beta, inflammation, osteoimmunology, systems analysis

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

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Biomarkers for Inflammatory Lung Disease

Most cited references 31

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Colony-stimulating factor-1 in immunity and inflammation.

Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice.

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