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Cited by 84Hair Growth and DisordersSkin and Cellular Biology ResearchDevelopmental Biology and Gene Regulation

Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer

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Cockburn, Katie, Annusver, Karl, Gonzalez, David G., Ganesan, Smirthy, May, Dennis P., Mesa, Kailin R., Kawaguchi, Kyogo, Kasper, Maria +1 more·2022·Nature Cell Biology
DOI 10.1038/s41556-022-01021-8PMC PMC9729105

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Abstract

Highly regenerative tissues continuously produce terminally differentiated cells to replace those that are lost. How they orchestrate the complex transition from undifferentiated stem cells towards post-mitotic, molecularly distinct and often spatially segregated differentiated populations is not well understood. In the adult skin epidermis, the stem cell compartment contains molecularly heterogeneous subpopulations 1–4 whose relationship to the complete trajectory of differentiation remains unknown. Here we show that differentiation, from commitment to exit from the stem cell layer, is a multi-day process wherein cells transit through a continuum of transcriptional changes with upregulation of differentiation genes preceding downregulation of typical stemness genes. Differentiation-committed cells remain capable of dividing to produce daughter cells fated to further differentiate, demonstrating that differentiation is uncoupled from cell cycle exit. These cell divisions are not required as part of an obligate transit-amplifying programme but help to buffer the differentiating cell pool during heightened demand. Thus, instead of distinct contributions from multiple progenitors, a continuous gradual differentiation process fuels homeostatic epidermal turnover.

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  • Overlapping TF gradients accompany cellular differentiation in systems including exit from pluripotency, organogenesis, and tissue regeneration by adult stem cells.

    “Similar overlapping TF gradients accompany cellular differentiation in systems ranging from the exit from pluripotency5 over organogenesis6 to tissue regeneration by other adult stem cells.7,8”

    From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [7]

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Cited by

Sorted by citations

Authors
Cockburn, K., Annusver, K., Gonzalez, D. G., Ganesan, S., May, D. P., Mesa, K. R., Kawaguchi, K., Kasper, M., & Greco, V.
Affiliations
  • Yale University (US)
  • Karolinska Institutet (SE)
  • RIKEN (JP)
  • Yale Cancer Center (US)
Corresponding author
  • Kasper, Maria
  • Greco, Valentina
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2022-11-10
Volume
24
Issue
12
Pages
1692-1700
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-022-01021-8
PMC
PMC9729105
OpenAlex
W4308767144
Cited by
84
References
3
Citations by year
2026: 22 · 2025: 16 · 2024: 16 · 2023: 18 · 2022: 8 · 2021: 4
FWCI
16.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • New York Stem Cell Foundation
  • Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre
  • Karolinska Institutet (2-2111/2019)
  • Human Frontier Science Program
  • MEXT | Japan Society for the Promotion of Science (JP18H04760, JP18K13515, JP19H05275, JP19H05795)
  • Stiftelsen för Strategisk Forskning (FFL12-0133)
  • Cancerfonden (CAN 2018/793; 21 1821 Pj)
  • Svenska Forskningsrådet Formas (2018-02963)
  • U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063663, R01AR072668, DP1AG066590)
  • Howard Hughes Medical Institute (Scholar Award)
Topics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
epidermal stem cells, skin regeneration, cell differentiation, cell cycle exit, stem cell heterogeneity, stemness genes, differentiation genes, epidermal turnover, tissue homeostasis, gene expression changes
MeSH terms
Cell Cycle, Cell Differentiation, Cell Division, Stem Cells

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