Abstract
Stem cell (SC) exhaustion is a hallmark of aging. However, the process of SC depletion during aging has not been observed in live animals, and the underlying mechanism contributing to tissue deterioration remains obscure. We find that, in aged mice, epithelial cells escape from the hair follicle (HF) SC compartment to the dermis, contributing to HF miniaturization. Single-cell RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) reveal reduced expression of cell adhesion and extracellular matrix genes in aged HF-SCs, many of which are regulated by Foxc1 and Nfatc1. Deletion of Foxc1 and Nfatc1 recapitulates HF miniaturization and causes hair loss. Live imaging captures individual epithelial cells migrating away from the SC compartment and HF disintegration. This study illuminates a hitherto unknown activity of epithelial cells escaping from their niche as a mechanism underlying SC reduction and tissue degeneration. Identification of homeless epithelial cells in aged tissues provides a new perspective for understanding aging-associated diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 889-903 |
| Number of pages | 15 |
| Journal | Nature Aging |
| Volume | 1 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2021 |
Funding
We thank T. Cech (University of Colorado Boulder, HHMI), K. Green and R. Lavker (Northwestern University) for comments; J. Siegenthaler (University of Colorado School of Medicine) for Foxc1fl/fland Foxc1 -LacZ mice; E. Fuchs (Rockefeller University, HHMI) for Krt14 -H2BGFP and Krt14 -Cre mice; D. Sheppard (University of California San Francisco) for Itgb6 -KO mice; H. Fujiwara (RIKEN, Japan) for anti-NPNT and anti-EGFL6 antibodies; M. Allen (University of Colorado Boulder) for discussing bioinformatic analysis; J. Orth (University of Colorado Boulder), J. Lopez and R. Goldmeyer (Olympus) for two-photon imaging; and all members of the Yi laboratory for suggestions. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers AR059697, AR066703 and AR071435 (to R.Y.) and by the National Institutes of Health under award number GM125871 (to R.D.). C.Z. was supported by an NCI Predoctoral to Postdoctoral Fellow Transition Award (F99CA253738). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank T. Cech (University of Colorado Boulder, HHMI), K. Green and R. Lavker (Northwestern University) for comments; J. Siegenthaler (University of Colorado School of Medicine) for Foxc1 and Foxc1-LacZ mice; E. Fuchs (Rockefeller University, HHMI) for Krt14-H2BGFP and Krt14-Cre mice; D. Sheppard (University of California San Francisco) for Itgb6 -KO mice; H. Fujiwara (RIKEN, Japan) for anti-NPNT and anti-EGFL6 antibodies; M. Allen (University of Colorado Boulder) for discussing bioinformatic analysis; J. Orth (University of Colorado Boulder), J. Lopez and R. Goldmeyer (Olympus) for two-photon imaging; and all members of the Yi laboratory for suggestions. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers AR059697, AR066703 and AR071435 (to R.Y.) and by the National Institutes of Health under award number GM125871 (to R.D.). C.Z. was supported by an NCI Predoctoral to Postdoctoral Fellow Transition Award (F99CA253738). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. fl/fl
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Aging
- Geriatrics and Gerontology