Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma

Nicole K. Patel, Johanna H. Nunez, Michael Sorkin, Simone Marini, Chase A. Pagani, Amy L. Strong, Charles D. Hwang, Shuli Li, Karthik R. Padmanabhan, Ravi Kumar, Alec C. Bancroft, Joey A. Greenstein, Reagan Nelson, Husain A. Rasheed, Nicholas Livingston, Kaetlin Vasquez, Amanda K. Huber, Benjamin Levi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Transforming growth factor–β1 (TGF-β1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGF-β1 signaling in macrophages, and not mesenchymal stem/progenitor cells, is critical in HO formation. In-depth single-cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrated increased TGF-β1 signaling in early infiltrating macrophages, with open chromatin regions in TGF-β1–stimulated genes at binding sites specific for transcription factors of activated TGF-β1 (SMAD2/3). Genetic deletion of TGF-β1 receptor type 1 (Tgfbr1; Alk5), in macrophages, resulted in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor, we administered a systemic treatment with TGF-β1/3 ligand trap TGF-βRII-Fc, which resulted in decreased HO formation and a delay in macrophage infiltration to the injury site. Overall, our data support the role of the TGF-β1/ ALK5 signaling pathway in HO.

Original languageEnglish
Article numbere144925
JournalJCI Insight
Issue number20
StatePublished - 24 Oct 2022
Externally publishedYes


Dive into the research topics of 'Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma'. Together they form a unique fingerprint.

Cite this