TY - JOUR
T1 - Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing
AU - Sorkin, Michael
AU - Huber, Amanda K.
AU - Hwang, Charles
AU - Carson, William F.
AU - Menon, Rajasree
AU - Li, John
AU - Vasquez, Kaetlin
AU - Pagani, Chase
AU - Patel, Nicole
AU - Li, Shuli
AU - Visser, Noelle D.
AU - Niknafs, Yashar
AU - Loder, Shawn
AU - Scola, Melissa
AU - Nycz, Dylan
AU - Gallagher, Katherine
AU - McCauley, Laurie K.
AU - Xu, Jiajia
AU - James, Aaron W.
AU - Agarwal, Shailesh
AU - Kunkel, Stephen
AU - Mishina, Yuji
AU - Levi, Benjamin
N1 - Funding Information:
We would like to thank the University of Michigan Center for Molecular Imaging and Amanda Fair for her assistance. We would further like to thank the Biomedical Research Core Facilities DNA Sequencing Core and the staff for processing sequencing samples. We would also like to thank David Cholok MD, Serra Ucer PhD, Amrita Joshi MS, Talis Rehse BS, Prasanth Kotha, Sidra Kader BS, Mohamed A. Garada BS, and Ramkumar T. Annamalai PhD for their technical assistance. MS was funded by Plastic Surgery Foundation National Endowment Award, AWJ was funded by NIH/NIAMS (R01 AR070773, K08 AR068316), NIH/NIDCR (R21 DE027922), USAMRAA through the Peer Reviewed Medical Research Program (W81XWH-18-1-0121, W81XWH-18-1-0336), Department of Defense through the Broad Agency Announcement (BA160256), American Cancer Society (Research Scholar Grant, RSG-18-027-01-CSM), the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation, the Maryland Stem Cell Research Foundation, and the Musculoskeletal Transplant Foundation. YM was funded by NIH R01DE020843, DoD W81XWH-11-2-0073; LKM was funded by DK053904. CH was supported by Howard Hughes Medical Institute Medical Research Fellowship. BL was funded by NIH, NIAMS, NIH1R01AR071379, ACS Clowes Award, International Fibrodysplasia Ossificans Progressiva Association Research Award, NIH, NIGMS, K08GM109105, R01GM123069.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-14172-4
DO - 10.1038/s41467-019-14172-4
M3 - Article
C2 - 32024825
AN - SCOPUS:85079069427
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 722
ER -