TY - JOUR
T1 - NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
AU - Lee, Seungyong
AU - Hwang, Charles
AU - Marini, Simone
AU - Tower, Robert J.
AU - Qin, Qizhi
AU - Negri, Stefano
AU - Pagani, Chase A.
AU - Sun, Yuxiao
AU - Stepien, David M.
AU - Sorkin, Michael
AU - Kubiak, Carrie A.
AU - Visser, Noelle D.
AU - Meyers, Carolyn A.
AU - Wang, Yiyun
AU - Rasheed, Husain A.
AU - Xu, Jiajia
AU - Miller, Sarah
AU - Huber, Amanda K.
AU - Minichiello, Liliana
AU - Cederna, Paul S.
AU - Kemp, Stephen W.P.
AU - Clemens, Thomas L.
AU - James, Aaron W.
AU - Levi, Benjamin
N1 - Funding Information:
Research unrelated to the work presented herein was supported in the James laboratory by Musculoskeletal Transplant Foundation (MTF) Biologics and Novadip Biosciences. A.W.J. is a paid consultant for Novadip and Lifesprout. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. The authors have declared that no further conflict of interest exists.
Funding Information:
We thank the JHU microscopy facility, University of Michigan Center for Molecular Imaging, Biomedical Research Core Facilities DNA Sequencing Core, Amanda Fair, Nathan Lawera, Talis Rehse, Zaid Khatib, Kaetlin Vasquez, Jeffrey Lisiecki MD, Mohamed Garada for their technical assistance. A.W.J. was funded by NIH/NIAMS (R01 AR070773), NIH/NIDCR (R21 DE027922), USAMRAA through the Peer-Reviewed Medical Research Program (W81XWH-18-1-0121, W81XWH-18-1-0336) and Broad Agency Announcement (W81XWH-18-10613), American Cancer Society (Research Scholar Grant, RSG-18-027-01-CSM), and the Maryland Stem Cell Research Foundation. B.L. funded by the NIH (1R01AR071379, R61 AR078072), International Fibrodysplasia Ossificans Progressiva Association Research Award, and American College of Surgeon Clowes Award. A.W.J. and B.L. are funded by NIH (R01 AR079171) and DoD (W81XWH-20-1-0795). M.S. supported by Plastic Surgery Foundation National Endowment Award. C.H. supported by Howard Hughes Medical Institute Medical Research Fellowship. D.M.S. supported by Plastic Surgery Foundation Resident Research Award. T.L.C. was supported by the NIH/NIAMS (R01 AR068934), NIH/NIDCR (R21 DE027922), and the VA (Merit Award and Senior Research Career Scientist Award). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health or the Department of Defense.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112719416&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25143-z
DO - 10.1038/s41467-021-25143-z
M3 - Article
C2 - 34400627
AN - SCOPUS:85112719416
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4939
ER -