TY - JOUR
T1 - Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma
AU - Patel, Nicole K.
AU - Nunez, Johanna H.
AU - Sorkin, Michael
AU - Marini, Simone
AU - Pagani, Chase A.
AU - Strong, Amy L.
AU - Hwang, Charles D.
AU - Li, Shuli
AU - Padmanabhan, Karthik R.
AU - Kumar, Ravi
AU - Bancroft, Alec C.
AU - Greenstein, Joey A.
AU - Nelson, Reagan
AU - Rasheed, Husain A.
AU - Livingston, Nicholas
AU - Vasquez, Kaetlin
AU - Huber, Amanda K.
AU - Levi, Benjamin
N1 - Publisher Copyright:
© 2022, Patel et al.
PY - 2022/10/24
Y1 - 2022/10/24
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85140417090
U2 - 10.1172/jci.insight.144925
DO - 10.1172/jci.insight.144925
M3 - Article
C2 - 36099022
AN - SCOPUS:85140417090
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - e144925
ER -