Epidermal E-Cadherin Dependent β-Catenin Pathway Is Phytochemical Inducible and Accelerates Anagen Hair Cycling

Mol Ther. 2017 Nov 1;25(11):2502-2512. doi: 10.1016/j.ymthe.2017.07.010. Epub 2017 Jul 20.

Abstract

Unlike the epidermis, which regenerates continually, hair follicles anchored in the subcutis periodically regenerate by spontaneous repetitive cycles of growth (anagen), degeneration (catagen), and rest (telogen). The loss of hair follicles in response to injuries or pathologies such as alopecia endangers certain inherent functions of the skin. Thus, it is of interest to understand mechanisms underlying follicular regeneration in adults. In this work, a phytochemical rich in the natural vitamin E tocotrienol (TRF) served as a productive tool to unveil a novel epidermal pathway of hair follicular regeneration. Topical TRF application markedly induced epidermal hair follicle development akin to that during fetal skin development. This was observed in the skin of healthy as well as diabetic mice, which are known to be resistant to anagen hair cycling. TRF suppressed epidermal E-cadherin followed by 4-fold induction of β-catenin and its nuclear translocation. Nuclear β-catenin interacted with Tcf3. Such sequestration of Tcf3 from its otherwise known function to repress pluripotent factors induced the plasticity factors Oct4, Sox9, Klf4, c-Myc, and Nanog. Pharmacological inhibition of β-catenin arrested anagen hair cycling by TRF. This work reports epidermal E-cadherin/β-catenin as a novel pathway capable of inducing developmental folliculogenesis in the adult skin.

Keywords: E-cadherin; anagen; hair follicles; stem cells; β-catenin.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cadherins / antagonists & inhibitors
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Gene Expression Regulation
  • Hair Follicle / drug effects*
  • Hair Follicle / growth & development
  • Hair Follicle / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Phytochemicals / pharmacology*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Regeneration / drug effects*
  • Regeneration / genetics
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction
  • Tocotrienols / pharmacology*
  • beta Catenin / agonists
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CTNNB1 protein, mouse
  • Cadherins
  • Cdh1 protein, mouse
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Phytochemicals
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Tcf3 protein, mouse
  • Tocotrienols
  • beta Catenin