NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma

Seungyong Lee, Charles Hwang, Simone Marini, Robert J. Tower, Qizhi Qin, Stefano Negri, Chase A. Pagani, Yuxiao Sun, David M. Stepien, Michael Sorkin, Carrie A. Kubiak, Noelle D. Visser, Carolyn A. Meyers, Yiyun Wang, Husain A. Rasheed, Jiajia Xu, Sarah Miller, Amanda K. Huber, Liliana Minichiello, Paul S. Cederna, Stephen W. P. Kemp, Thomas L. Clemens, Aaron W. James () and Benjamin Levi ()
Additional contact information
Seungyong Lee: Johns Hopkins University
Charles Hwang: University of Texas
Simone Marini: University of Florida
Robert J. Tower: Johns Hopkins University
Qizhi Qin: Johns Hopkins University
Stefano Negri: Johns Hopkins University
Chase A. Pagani: University of Texas
Yuxiao Sun: University of Texas
David M. Stepien: University of Texas
Michael Sorkin: University of Texas
Carrie A. Kubiak: University of Texas
Noelle D. Visser: University of Texas
Carolyn A. Meyers: Johns Hopkins University
Yiyun Wang: Johns Hopkins University
Husain A. Rasheed: University of Texas
Jiajia Xu: Johns Hopkins University
Sarah Miller: Johns Hopkins University
Amanda K. Huber: University of Texas
Liliana Minichiello: Oxford University
Paul S. Cederna: University of Texas
Stephen W. P. Kemp: University of Texas
Thomas L. Clemens: Johns Hopkins University
Aaron W. James: Johns Hopkins University
Benjamin Levi: University of Texas

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.

Date: 2021
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DOI: 10.1038/s41467-021-25143-z

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