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Article

Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells

by 1,2,3,4,†,‡, 1,2,3,4,†,§, 5, 1,2,3,4, 1,2,3,4,* and 1,2,3,4,*
1
Laboratoire de Génomique et Radiobiologie de la Kératinopoïèse, Institut de Biologie François Jacob, CEA/DRF/IRCM, 91000 Evry, France
2
INSERM U967, 92260 Fontenay-aux-Roses, France
3
Université Paris-Saclay, 75013 Paris 11, France
4
Université Paris-Diderot, 78140 Paris 7, France
5
Ecole Pratique des Hautes Etudes, PSL Research University, UMRS 951, Genethon, 91002 Evry, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Present address: DEBR/Unité Rad/Institut de Recherche Biomédicale des Armées, 1 Place du Général Valérie André, 91223 Brétigny sur Orge, France.
§
Present address: Federal University of São Paulo (UNIFESP), Rua Silva Jardim, 136, Santos 11015020, SP, Brazil.
Cells 2020, 9(8), 1912; https://doi.org/10.3390/cells9081912
Received: 18 July 2020 / Revised: 7 August 2020 / Accepted: 14 August 2020 / Published: 18 August 2020
(This article belongs to the Special Issue Stem Cells and Irradiation)
For the general population, medical diagnosis is a major cause of exposure to low genotoxic stress, as various imaging techniques deliver low doses of ionizing radiation. Our study investigated the consequences of low genotoxic stress on a keratinocyte precursor fraction that includes stem and progenitor cells, which are at risk for carcinoma development. Human skin organoids were bioengineered according to a clinically-relevant model, exposed to a single 50 mGy dose of γ rays, and then xeno-transplanted in nude mice to follow full epidermis generation in an in vivo context. Twenty days post-xenografting, mature skin grafts were sampled and analyzed by semi-quantitative immuno-histochemical methods. Pre-transplantation exposure to 50 mGy of immature human skin organoids did not compromise engraftment, but half of xenografts generated from irradiated precursors exhibited areas displaying focal dysplasia, originating from the basal layer of the epidermis. Characteristics of epithelial-to-mesenchymal transition (EMT) were documented in these dysplastic areas, including loss of basal cell polarity and cohesiveness, epithelial marker decreases, ectopic expression of the mesenchymal marker α-SMA and expression of the EMT promoter ZEB1. Taken together, these data show that a very low level of radiative stress in regenerating keratinocyte stem and precursor cells can induce a micro-environment that may constitute a favorable context for long-term carcinogenesis. View Full-Text
Keywords: human epidermis; keratinocytes; stem cells; precursor cells; low-dose γ irradiation; regeneration; dysplasia; epithelial-to-mesenchymal transition (EMT); ZEB1 human epidermis; keratinocytes; stem cells; precursor cells; low-dose γ irradiation; regeneration; dysplasia; epithelial-to-mesenchymal transition (EMT); ZEB1
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MDPI and ACS Style

Cavallero, S.; Neves Granito, R.; Stockholm, D.; Azzolin, P.; Martin, M.T.; Fortunel, N.O. Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells. Cells 2020, 9, 1912. https://doi.org/10.3390/cells9081912

AMA Style

Cavallero S, Neves Granito R, Stockholm D, Azzolin P, Martin MT, Fortunel NO. Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells. Cells. 2020; 9(8):1912. https://doi.org/10.3390/cells9081912

Chicago/Turabian Style

Cavallero, Sophie, Renata Neves Granito, Daniel Stockholm, Peggy Azzolin, Michèle T. Martin, and Nicolas O. Fortunel 2020. "Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells" Cells 9, no. 8: 1912. https://doi.org/10.3390/cells9081912

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