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- Hoste, E, et al.
(author)
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OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5913-
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Journal article (peer-reviewed)abstract
- OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation ofOtulinselectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion ofTnfr1, knockin expression of kinase-inactiveRipk1or keratinocyte-specific deletion ofFaddandMlklcompletely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutantOtulinallele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.
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| 3. |
- Cockburn, K, et al.
(author)
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Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer
- 2022
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In: Nature cell biology. - : Springer Science and Business Media LLC. - 1476-4679 .- 1465-7392. ; 24:12, s. 1692-
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Journal article (peer-reviewed)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 subpopulations1–4 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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