Stem cell competition orchestrates skin homeostasis and ageing

Nature. 2019 Apr;568(7752):344-350. doi: 10.1038/s41586-019-1085-7. Epub 2019 Apr 3.

Abstract

Stem cells underlie tissue homeostasis, but their dynamics during ageing-and the relevance of these dynamics to organ ageing-remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 in individual stem cells generates a driving force for cell competition. In vivo clonal analysis in mice and in vitro 3D modelling show that clones that express high levels of COL17A1, which divide symmetrically, outcompete and eliminate adjacent stressed clones that express low levels of COL17A1, which divide asymmetrically. Stem cells with higher potential or quality are thus selected for homeostasis, but their eventual loss of COL17A1 limits their competition, thereby causing ageing. The resultant hemidesmosome fragility and stem cell delamination deplete adjacent melanocytes and fibroblasts to promote skin ageing. Conversely, the forced maintenance of COL17A1 rescues skin organ ageing, thereby indicating potential angles for anti-ageing therapeutic intervention.

MeSH terms

  • Animals
  • Atrophy
  • Autoantigens / chemistry
  • Autoantigens / metabolism
  • Cell Division
  • Cell Proliferation
  • Clone Cells / cytology
  • Epidermal Cells / cytology
  • Epidermal Cells / pathology
  • Female
  • Genome
  • Hemidesmosomes / pathology
  • Homeostasis*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Non-Fibrillar Collagens / chemistry
  • Non-Fibrillar Collagens / metabolism
  • Oxidative Stress
  • Proteolysis
  • Skin / cytology*
  • Skin / pathology*
  • Skin Aging / pathology*
  • Skin Aging / physiology*
  • Stem Cells / cytology*
  • Stem Cells / pathology*

Substances

  • Autoantigens
  • Non-Fibrillar Collagens
  • collagen type XVII