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

Stem cell competition orchestrates skin homeostasis and ageing.

Author information

1
Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
2
Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. matsscm@tmd.ac.jp.
3
Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
4
Department of Dermatology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Tokyo, Japan.
5
CNRS UMR7104, Inserm U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Development and Stem Cells Department, Université de Strasbourg, Strasbourg, France.
6
Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. nishscm@tmd.ac.jp.

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.

PMID:
30944469
DOI:
10.1038/s41586-019-1085-7

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