NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Year: 2021
Type: article
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.
Source: Nature Communications
Authors: 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, Benjamin Levi
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Plastic Surgery Foundation, Maryland Stem Cell Research Fund, International Fibrodysplasia Ossificans Progressiva Association, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, U.S. Army Medical Research Acquisition Activity
Awards: G1037033942, Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossific, G1877635988, G2010695601, G241257592, G3518181607, G3941577509, G4119534169, DEVELOPMENT OF SMOOTHENED AGONIST NON-PHOSPHOLIPID LIPOSOMAL NANOPARTICLES FOR BONE REPAIR, ENDOGENOUS AND EXOGENOUS PERICYTES IN THE PATHOBIOLOGY AND TREATMENT OF OSTEOARTHRITIS, G5112819247, DKK1 ANTAGONISM FOR STROMAL VASCULAR FRACTION, G578267061, G5850682332, G6640987120, G7291523422, G7604553565, Neuronal Regulation of Skeletal Development and Repair, G7734636060, Direct and indirect contributions of perivascular stem cells to bone healing, G8166743225, G833077115, IMPROVING TENDON REPAIR VIA SENSORY NERVE NGF-TRKA SIGNALING FOR RETENTION ON DUTY, G967199362
OpenAlex ID: W3194902694