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

Publication ,  Journal Article
Lee, S; Hwang, C; Marini, S; Tower, RJ; Qin, Q; Negri, S; Pagani, CA; Sun, Y; Stepien, DM; Sorkin, M; Kubiak, CA; Visser, ND; Meyers, CA ...
Published in: Nat Commun
August 16, 2021

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 16, 2021

Volume

12

Issue

1

Start / End Page

4939

Location

England

Related Subject Headings

  • Wounds and Injuries
  • Stem Cells
  • Signal Transduction
  • Receptor, trkA
  • Osteogenesis
  • Nerve Growth Factor
  • Mice, Inbred C57BL
  • Mice
  • Cell Differentiation
  • Cartilage
 

Citation

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Lee, S., Hwang, C., Marini, S., Tower, R. J., Qin, Q., Negri, S., … Levi, B. (2021). NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun, 12(1), 4939. https://doi.org/10.1038/s41467-021-25143-z
Lee, Seungyong, Charles Hwang, Simone Marini, Robert J. Tower, Qizhi Qin, Stefano Negri, Chase A. Pagani, et al. “NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma.Nat Commun 12, no. 1 (August 16, 2021): 4939. https://doi.org/10.1038/s41467-021-25143-z.
Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, et al. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021 Aug 16;12(1):4939.
Lee, Seungyong, et al. “NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma.Nat Commun, vol. 12, no. 1, Aug. 2021, p. 4939. Pubmed, doi:10.1038/s41467-021-25143-z.
Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, Pagani CA, Sun Y, Stepien DM, Sorkin M, Kubiak CA, Visser ND, Meyers CA, Wang Y, Rasheed HA, Xu J, Miller S, Huber AK, Minichiello L, Cederna PS, Kemp SWP, Clemens TL, James AW, Levi B. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021 Aug 16;12(1):4939.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 16, 2021

Volume

12

Issue

1

Start / End Page

4939

Location

England

Related Subject Headings

  • Wounds and Injuries
  • Stem Cells
  • Signal Transduction
  • Receptor, trkA
  • Osteogenesis
  • Nerve Growth Factor
  • Mice, Inbred C57BL
  • Mice
  • Cell Differentiation
  • Cartilage