Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging

Cell Rep. 2021 Aug 31;36(9):109634. doi: 10.1016/j.celrep.2021.109634.

Abstract

Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner-by reinstatement of IGF-1 and p16 levels-restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.

Keywords: IGF-1; JunB; aging; fibroblasts; p16(INK4A); redox imbalance; skin; stem cell niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication*
  • Cells, Cultured
  • Cellular Senescence
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Fibroblasts / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Mice, Knockout
  • Skin / metabolism*
  • Skin / pathology
  • Skin Aging*
  • Stem Cell Niche*
  • Stem Cells / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CDKN2A protein, human
  • Col1a2 protein, mouse
  • Collagen Type I
  • Cyclin-Dependent Kinase Inhibitor p16
  • JunB protein, mouse
  • Transcription Factors
  • insulin-like growth factor-1, mouse
  • Superoxides
  • Insulin-Like Growth Factor I
  • Superoxide Dismutase
  • superoxide dismutase 2