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Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β

ABSTRACT: Epithelial tissues possess a barrier function that must be restored following injury. Repair often involves changes in cell fate, but it remains poorly understood how cell plasticity is induced and whether responses vary with distinct types of damage. Here, we reveal that genotoxic agents, but not mechanical damage, induce hyperplasia and lineage infidelity in the interfollicular epidermis, as well as in two epidermal subappendages: the mammary gland and hair follicle. DNA damage to the epidermis promotes stromal proliferation, and induces basal cell hyperplasia with formation of abnormal, multi-layered K14+/K10+ cells. Unexpectedly, this behavior is epithelial cell non-autonomous, but independent of immunity. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response. We identify a previously unrecognized fibroblast-specific NLRP3 inflammasome that drives this response via IL-1β. Thus, genotoxic agents, used chemotherapeutically to promote cancer cell death, can have the opposite effect on wild-type epithelia, paradoxically promoting hyperplasia and inducing both stemness and lineage infidelity via a non-autonomous, fibroblast-driven mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE139272 | GEO | 2020/12/16

REPOSITORIES: GEO

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Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β

Project description:Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β

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Expression data from primary mouse embryonic fibroblasts from wild-type and Cry double-knockout embryos

Project description:By gating cell cycle progression to specific times of the day, the intracellular circadian clock is thought to reduce the exposure of replicating cells to potentially hazardous environmental and endogenous genotoxic compounds. Although core clock gene defects that eradicate circadian rhythmicity can cause an altered in vivo genotoxic stress response and aberrant proliferation rate, it remains to be determined to what extent these cell-cycle-related phenotypes are due to a cell-autonomous lack of circadian oscillations. We investigated the DNA damage sensitivity and proliferative capacity of cultured primary Cry1-/-|Cry2-/- fibroblasts. Contrasting previous in vivo studies, we show that the absence of CRY proteins does not affect the cell-autonomous DNA damage response upon exposure of primary cells in vitro to genotoxic agents, but causes cells to proliferate faster. By comparing primary wild type, Cry1-/-|Cry2-/-, Cry1+/-|Cry2-/- and Cry1-/-|Cry2+/- fibroblasts, we provide evidence that CRY proteins influence cell cycle progression in a cell-autonomous, but circadian clock-independent manner and that the accelerated cell cycle progression of Cry-deficient cells is caused by global dysregulation of Bmal1-dependent gene expression. These results suggest that the inconsistency between in vivo and in vitro observations might be attributed to systemic circadian control rather than a direct cell-autonomous control. Asynchronous proliferating MEFs grown under low (3%) oxygen tension and lysed in Trizol. Four independent cell lines were used for each genotype (WT, Cry DKO).

2011-09-30 | E-GEOD-31958 | biostudies-arrayexpress

Expression data from primary mouse embryonic fibroblasts from wild-type and Cry double-knockout embryos

2011-10-01 | GSE31958 | GEO

Chromosome copy number analysis (WGS) of repair-proficient and repair-deficient yeast strains (S. cerevisiae) after genotoxic treatment with camptothecin or X-ray irradiation

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2019-10-22 | E-MTAB-7380 | biostudies-arrayexpress

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2008-04-08 | E-GEOD-7675 | biostudies-arrayexpress

Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

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EGFR and hair shaft differentiation

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2019-07-23 | GSE128436 | GEO

Human Fibroblast cells immortalised cells: Control vs DNA damage

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