NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
| Autor: | Chase A. Pagani, Stefano Negri, Amanda K. Huber, Charles Hwang, Benjamin Levi, Carolyn A. Meyers, Jiajia Xu, Robert J. Tower, Stephen W. P. Kemp, Aaron W. James, Michael Sorkin, Husain Rasheed, Qizhi Qin, Yuxiao Sun, David M. Stepien, Seungyong Lee, Sarah Miller, Carrie A. Kubiak, Thomas L. Clemens, Paul S. Cederna, Noelle D. Visser, Liliana Minichiello, Simone Marini, Yiyun Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cellular differentiation
Science General Physics and Astronomy Cartilage metabolism Biology Tropomyosin receptor kinase A Fibroblast growth factor Inbred C57BL General Biochemistry Genetics and Molecular Biology Article Mice Osteogenesis Nerve Growth Factor Animals Receptor trkA Bone Denervation Multidisciplinary Stem Cells fungi Growth factor signalling food and beverages Cell Differentiation General Chemistry Axons Cell biology Mice Inbred C57BL Nerve growth factor Cartilage nervous system trkA Wounds and Injuries Signal transduction Stem cell Peripheral nervous system Signal Transduction Receptor |
| Zdroj: | BASE-Bielefeld Academic Search Engine Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021) Nature Communications |
| Popis: | 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. Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling. |
| Databáze: | OpenAIRE |
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