Analysis and pharmacological modulation of senescence in human epithelial stem cells.
DAPT (γ-secretase inhibitor; N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine T-butyl ester)
EEC syndrome
RNAseq
lifespan
p63
self-renewal
stem cells
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
20
05
2022
received:
10
08
2021
accepted:
28
05
2022
pubmed:
17
6
2022
medline:
16
7
2022
entrez:
16
6
2022
Statut:
ppublish
Résumé
Human epithelial stem cells (ESCs) are characterized by long-term regenerative properties, much dependent on the tissue of origin and varying during their lifespan. We analysed such variables in cultures of ESCs isolated from the skin, conjunctiva, limbus and oral mucosa of healthy donors and patients affected by ectrodactyly-ectodermal dysplasia-clefting syndrome, a rare genetic disorder caused by mutations in the p63 gene. We cultured cells until exhaustion in the presence or in the absence of DAPT (γ-secretase inhibitor; N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine T-butyl ester). All cells were able to differentiate in vitro but exhibited variable self-renewal potential. In particular, cells carrying p63 mutations stopped prematurely, compared with controls. Importantly, administration of DAPT significantly extended the replicative properties of all stem cells under examination. RNA sequencing analysis revealed that distinct sets of genes were up- or down-regulated during their lifetime, thus allowing to identify druggable gene networks and off-the-shelf compounds potentially dealing with epithelial stem cell senescence. These data will expand our knowledge on the genetic bases of senescence and potentially pave the way to the pharmacological modulation of ageing in epithelial stem cells.
Identifiants
pubmed: 35706382
doi: 10.1111/jcmm.17434
pmc: PMC9279594
doi:
Substances chimiques
Platelet Aggregation Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3977-3994Subventions
Organisme : Italian Ministry of Health
ID : RF-2016-02361159
Organisme : Science Committee of the Republic of Armenia
ID : SC RA #21AG-1F068
Organisme : Università degli Studi di Padova
ID : 21AG-1F068
Informations de copyright
© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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