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Cited by 23Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Insights into epithelial cell senescence from transcriptome and secretome analysis of human oral keratinocytes

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Schwartz, Rachael E., Shokhirev, Maxim N., Andrade, Leonardo R., Gutkind, J. Silvio, Iglesias-Bartolome, Ramiro, Shadel, Gerald S.·2021·Aging
DOI 10.18632/aging.202658PMC PMC7950289
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Abstract

Senescent cells produce chronic inflammation that contributes to the diseases and debilities of aging. How this process is orchestrated in epithelial cells, the origin of human carcinomas, is poorly understood. We used human normal oral keratinocytes (NOKs) to elucidate senescence programs in a prototype primary mucosal epithelial cell that senesces spontaneously. While NOKs exhibit several typical facets of senescence, they also display distinct characteristics. These include expression of p21WAF1/CIP1 at early passages, making this common marker of senescence unreliable in NOKs. Transcriptome analysis by RNA-seq revealed specific commonalities with and differences from cancer cells, explicating the tumor avoidance role of senescence. Repression of DNA repair genes that correlated with downregulation of E2F1 mRNA and protein was observed for two donors; a divergent result was seen for the third. Using proteomic profiling of soluble (non-vesicular) and extracellular vesicle (EV) associated secretions, we propose additions to the senescence associated secretory phenotype, including HSP60, which localizes to the surface of EVs. Finally, EVs from senescent NOKs activate interferon pathway signaling in THP-1 monocytes in a STING-dependent manner and associate with mitochondrial and nuclear DNA. Our results highlight senescence changes in epithelial cells and how they might contribute to chronic inflammation and age-related diseases.

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Authors
Schwartz, R. E., Shokhirev, M. N., Andrade, L. R., Gutkind, J. S., Iglesias-Bartolome, R., & Shadel, G. S.
Affiliations
  • Salk Institute for Biological Studies (US)
  • University of California San Diego (US)
  • Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Corresponding author
Schwartz, Rachael E.
ORCID
Venue
Aging
Publisher
Impact Journals, LLC
Published
2021-02-12
Volume
13
Issue
4
Pages
4747-4777
ISSN
1945-4589 (ISSN-L)
DOI
10.18632/aging.202658
PMC
PMC7950289
OpenAlex
W3131101747
Cited by
23
References
53
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 1
FWCI
2.51
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Cancer Institute (P30CA014195)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, oral keratinocytes, epithelial cells, senescence-associated secretory phenotype, extracellular vesicles, HSP60, DNA repair genes, E2F1, p21, interferon signaling, STING, chronic inflammation, transcriptome, secretome
MeSH terms
Extracellular Vesicles, Epithelial Cells, Humans, Mouth Mucosa, Signal Transduction, Keratinocytes, Cellular Senescence, Sequence Analysis, RNA, Gene Expression Profiling

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