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

Author

Listed:
  • 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
    University of Verona)

  • 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
    Baltimore Veterans Administration Medical Center)

  • Aaron W. James

    (Johns Hopkins University)

  • Benjamin Levi

    (University of Texas)

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.

Suggested Citation

  • 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 & C, 2021. "NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25143-z
    DOI: 10.1038/s41467-021-25143-z
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    Cited by:

    1. Lingchi Kong & Xin Gao & Xiangyun Yao & Haijiao Xie & Qinglin Kang & Wei Sun & Zhengwei You & Yun Qian & Cunyi Fan, 2024. "Multilevel neurium-mimetic individualized graft via additive manufacturing for efficient tissue repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Lan Zhao & Yumei Lai & Hongli Jiao & Jian Huang, 2024. "Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Fei Pei & Li Ma & Junjun Jing & Jifan Feng & Yuan Yuan & Tingwei Guo & Xia Han & Thach-Vu Ho & Jie Lei & Jinzhi He & Mingyi Zhang & Jian-Fu Chen & Yang Chai, 2023. "Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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