Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.
Animals
Burns
/ pathology
CD47 Antigen
/ metabolism
Cell Differentiation
Cytokines
/ metabolism
Disease Models, Animal
Gene Expression Regulation
Macrophages
/ pathology
Male
Mesenchymal Stem Cells
/ drug effects
Mice, Inbred C57BL
Mice, Transgenic
Monocytes
/ pathology
Ossification, Heterotopic
/ pathology
Peptides
/ pharmacology
Phagocytosis
Transforming Growth Factor beta1
/ genetics
Wound Healing
/ physiology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
11
02
2019
accepted:
13
12
2019
entrez:
7
2
2020
pubmed:
7
2
2020
medline:
19
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32024825
doi: 10.1038/s41467-019-14172-4
pii: 10.1038/s41467-019-14172-4
pmc: PMC7002453
doi:
Substances chimiques
CD47 Antigen
0
Cd47 protein, mouse
0
Cytokines
0
Peptides
0
Tgfb1 protein, mouse
0
Transforming Growth Factor beta1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
722Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE022327
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR071379
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK053904
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK053904
Pays : United States
Références
Sluys, K. P., Shults, J. & Richmond, T. S. Health related quality of life and return to work after minor extremity injuries: A longitudinal study comparing upper versus lower extremity injuries. Injury 47, 824–831 (2016).
doi: 10.1016/j.injury.2016.02.019
Lin, S. H., Lee, H. Y., Chang, Y. Y., Jang, Y. & Wang, J. D. Estimation of life expectancies and loss-of-life expectancies for workers with permanent occupational disabilities of the extremities–a 21-year follow-up study. Scand. J. Work Environ. Health 38, 70–77 (2012).
doi: 10.5271/sjweh.3194
Agarwal, S., Sorkin, M. & Levi, B. Heterotopic ossification and hypertrophic scars. Clin. Plast. Surg. 44, 749–755 (2017).
doi: 10.1016/j.cps.2017.05.006
Dolan, C. P., Dawson, L. A. & Muneoka, K. Digit tip regeneration: merging regeneration biology with regenerative medicine. Stem Cells Transl. Med. 7, 262–270 (2018).
doi: 10.1002/sctm.17-0236
Zhang, B., Li, S., Miao, D., Zhao, C. & Wang, L. Risk factors of cage subsidence in patients with ossification of posterior longitudinal ligament (OPLL) after anterior cervical discectomy and fusion. Med. Sci. Monit. 24, 4753–4759 (2018).
doi: 10.12659/MSM.910964
Brotherton, B. J. & Ball, J. Fracture of an ossified Achilles tendon. Injury 10, 245–247 (1979).
doi: 10.1016/0020-1383(79)90019-6
Ranganathan, K. et al. Heterotopic ossification: basic-science principles and clinical correlates. J. Bone Jt. Surg. Am. 97, 1101–1111 (2015).
doi: 10.2106/JBJS.N.01056
Wang, Y. et al. Incidence and factors associated with development of heterotopic ossification after damage control laparotomy. Injury 49, 51–55 (2018).
doi: 10.1016/j.injury.2017.11.033
Convente, M. R. et al. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1(R206H) mouse model of fibrodysplasia ossificans progressiva. J. Bone Min. Res. 33, 269–282 (2018).
doi: 10.1002/jbmr.3304
Kan, L. et al. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells 27, 150–156 (2009).
doi: 10.1634/stemcells.2008-0576
Torossian, F. et al. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. JCI Insight 2, 96034 (2017).
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).
doi: 10.1002/path.4133
Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).
doi: 10.1172/JCI59643
Xiao, X. et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc. Natl. Acad. Sci. USA 111, E1211–E1220 (2014).
doi: 10.1073/pnas.1321347111
van der Kraan, P. M., Blaney Davidson, E. N., Blom, A. & van den Berg, W. B. TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads. Osteoarthr. Cartil. 17, 1539–1545 (2009).
doi: 10.1016/j.joca.2009.06.008
Wang, W., Rigueur, D. & Lyons, K. M. TGFbeta signaling in cartilage development and maintenance. Birth Defects Res. C Embryo Today 102, 37–51 (2014).
doi: 10.1002/bdrc.21058
Foley, K. L., Hebela, N., Keenan, M. A. & Pignolo, R. J. Histopathology of periarticular non-hereditary heterotopic ossification. Bone 109, 65–70 (2018).
doi: 10.1016/j.bone.2017.12.006
Xu, X. et al. Transforming growth factor-beta in stem cells and tissue homeostasis. Bone Res. 6, 2 (2018).
doi: 10.1038/s41413-017-0005-4
Fahey, T. J. 3rd et al. Macrophage inflammatory protein 1 modulates macrophage function. J. Immunol. 148, 2764–2769 (1992).
pubmed: 1573267
Lin, J. D. et al. Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight 4, 124574 (2019).
Mould, K. J., Jackson, N. D., Henson, P. M., Seibold, M. & Janssen, W. J. Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsets. JCI Insight 4, 126556 (2019).
Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019).
doi: 10.1038/s41590-018-0272-2
Jordao, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019).
doi: 10.1126/science.aat7554
Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).
doi: 10.1016/j.coi.2005.11.006
Sasmono, R. T. et al. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J. Leukoc. Biol. 82, 111–123 (2007).
doi: 10.1189/jlb.1206713
MacDonald, K. P. et al. The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J. Immunol. 175, 1399–1405 (2005).
doi: 10.4049/jimmunol.175.3.1399
Deng, L. et al. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am. J. Pathol. 176, 952–967 (2010).
doi: 10.2353/ajpath.2010.090622
Misharin, A. V. et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 9, 591–604 (2014).
doi: 10.1016/j.celrep.2014.09.032
Dhaliwal, K. et al. Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury. Am. J. Respir. Crit. Care Med. 186, 514–524 (2012).
doi: 10.1164/rccm.201112-2132OC
van Amerongen, M. J., Harmsen, M. C., van Rooijen, N., Petersen, A. H. & van Luyn, M. J. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol. 170, 818–829 (2007).
doi: 10.2353/ajpath.2007.060547
Wahl, S. M. et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc. Natl Acad. Sci. USA 84, 5788–5792 (1987).
doi: 10.1073/pnas.84.16.5788
Shimada, K. et al. CD47 regulates the TGF-beta signaling pathway in osteoblasts and is distributed in Meckel’s cartilage. J. Oral Sci. 53, 169–175 (2011).
doi: 10.2334/josnusd.53.169
Soto-Pantoja, D. R. et al. Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice. Matrix Biol. 37, 25–34 (2014).
doi: 10.1016/j.matbio.2014.05.003
Sierra-Filardi, E. et al. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood 117, 5092–5101 (2011).
doi: 10.1182/blood-2010-09-306993
Murata, Y. et al. Autoimmune animal models in the analysis of the CD47-SIRPalpha signaling pathway. Methods 65, 254–259 (2014).
doi: 10.1016/j.ymeth.2013.09.016
Sangaletti, S. et al. Mesenchymal transition of high-grade breast carcinomas depends on extracellular matrix control of myeloid suppressor cell activity. Cell Rep. 17, 233–248 (2016).
doi: 10.1016/j.celrep.2016.08.075
Chiodoni, C., Sangaletti, S. & Colombo, M. P. Matricellular proteins tune myeloid-derived suppressor cell recruitment and function in breast cancer. J. Leukoc. Biol. 102, 287–292 (2017).
doi: 10.1189/jlb.3MR1016-447R
Zhao, Q., Guo, J., Wang, G., Chu, Y. & Hu, X. Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma. Oncotarget 8, 1668–1677 (2017).
pubmed: 27926489
Szebeni, G. J., Vizler, C., Nagy, L. I., Kitajka, K. & Puskas, L. G. Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets. Int. J. Mol. Sci. 17, E1958 (2016).
Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).
doi: 10.1016/j.it.2004.09.015
Peterson, J. R. et al. Treatment of heterotopic ossification through remote ATP hydrolysis. Sci. Transl. Med. 6, 255ra132 (2014).
doi: 10.1126/scitranslmed.3008810
Peterson, J. R. et al. Early detection of burn induced heterotopic ossification using transcutaneous Raman spectroscopy. Bone 54, 28–34 (2013).
doi: 10.1016/j.bone.2013.01.002
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411 (2018).
doi: 10.1038/nbt.4096
Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).
doi: 10.1038/nbt.2859