Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4

Yuka Okada, Takayoshi Sumioka, Kana Ichikawa, Hiromi Sano, Atsushi Nambu, Kenta Kobayashi, Kunitoshi Uchida, Yoshiro Suzuki, Makoto Tominaga, Peter Sol Reinach, Syu ichi Hirai, James V. Jester, Masayasu Miyajima, Kumi Shirai, Hiroki Iwanishi, Winston Whei Yang Kao, Chia Yang Liu, Shizuya Saika

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium.

Original languageEnglish
Pages (from-to)210-230
Number of pages21
JournalLaboratory Investigation
Volume99
Issue number2
DOIs
Publication statusPublished - 01-02-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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