Epidermal stem cells response to radiative genotoxic stress
Description
Human skin is the first organ exposed to various environmental stresses, which requires the development by skin stem cells of specific mechanisms to protect themselves and to ensure tissue homeostasis. As stem cells are responsible for the maintenance of epidermis during individual lifetime, the preservation of genomic integrity in these cells is essential. My PhD aimed at exploring the mechanisms set up by epidermal stem cells in order to protect themselves from two genotoxic stresses, ionizing radiation (Gamma Rays) and ultraviolet radiation (UVB). To begin my PhD, I have taken part of the demonstration of protective mechanisms used by keratinocyte stem cells after ionizing radiation. It has been shown that these cells are able to rapidly repair most types of radiation-induced DNA damage. Furthermore, we demonstrated that this repair is activated by the fibroblast growth factor 2 (FGF2). In order to know if this protective mechanism is also operating in cutaneous carcinoma stem cells, we investigated the response to gamma Rays of carcinoma stem cells isolated from a human carcinoma cell line. As in normal keratinocyte stem cells, we demonstrated that cancer stem cells could rapidly repair radio-induced DNA damage. Furthermore, fibroblast growth factor 2 also mediates this repair, notably thanks to its nuclear isoforms. The second project of my PhD was to study human epidermal stem cells and progenitors responses to UVB radiation. Once cytometry and irradiation conditions were set up, the toxicity of UVB radiation has been evaluate in the primary cell model. We then characterized UVB photons effects on cell viability, proliferation and repair of DNA damage. This study allowed us to bring out that responses of stem cells and their progeny to UVB are different, notably at the level of part of their repair activity of DNA damage. Moreover, progenitors and stem cells transcriptomic responses after UVB irradiation have been study in order to analyze the global mechanisms of stress response in the two cell populations. Taken together, data obtained during my PhD allowed us to show that stem cells respond differently than keratinocyte progenitors to radiation stress, and that they developed both intrinsic and radiation-induced strategies allowing a better protection. When comparing gamma Rays and UVB, we found that, although their toxic effects on skin share many similarities, the mechanisms set up by human epidermal stem cells to protect themselves vary according to the type of radiation stress. (author)
Abstract (French)
La peau etant le premier tissu expose aux diverses agressions de l'environnement exterieur, les cellules qui la composent doivent disposer de mecanismes de protection vis-a-vis de ces agressions, afin d'assurer le maintien de l'homeostasie tissulaire. Les cellules souches de l'epiderme assurant le renouvellement du compartiment epithelial pendant toute la vie de l'individu, la preservation de l'integrite de leur genome est essentielle a la fonctionnalite perenne de la peau. Mon doctorat avait pour objectif d'explorer les mecanismes mis en oeuvre par les cellules souches de l'epiderme interfolliculaire afin de se proteger de deux stress genotoxiques radiatifs, a savoir: les rayonnements gamma et les rayonnements ultraviolets B (UVB). Durant mon doctorat, j'ai tout d'abord participe a la demonstration des mecanismes de protection mis en oeuvre par les cellules souches des keratinocytes apres irradiation ionisante. En effet, il a ete montre que ces cellules sont capables de reparer tres rapidement l'ensemble des dommages de l'ADN radio-induits, et que cette reparation etait activee par le facteur de croissance FGF2 (Fibroblast Growth Factor 2). Afin de savoir si ce mecanisme de protection etait aussi operant dans les cellules souches de carcinome cutane, nous l'avons recherche dans la sous-population de cellules souches qui peut etre isolee d'une lignee de carcinome cutane humain. Comme dans le cas des cellules souches normales, nous avons montre que les cellules souches de cancer presentent une reparation tres rapide des dommages de l'ADN radio-induits. De plus, le facteur de croissance FGF2 participe a cette reparation, notamment par la presence d'isoformes de ce facteur dans le noyau cellulaire. Le second projet de mon doctorat avait pour objectif l'etude de la reponse des cellules souches et des progeniteurs de l'epiderme humain aux rayonnements UVB. Une fois mises en place les conditions de tri en cytometrie de flux et d'irradiation par les UVB, la toxicite de ces rayonnements a ete evaluee dans un modele cellulaire primaire. Nous avons caracterise les effets des photons UVB sur la viabilite et la proliferation cellulaire et etudie la reparation des dommages de l'ADN. Cette etude nous a permis de mettre en evidence des reponses aux UVB differentes entre les cellules souches et leur descendance immediate, les keratinocytes progeniteurs, notamment au niveau de l'activite de reparation des dommages de l'ADN. Par ailleurs, une etude du transcriptome des cellules irradiees a ete realisee, qui permet d'analyser les mecanismes globaux communs et specifiques de reponse au stress dans les deux populations. L'ensemble des donnees obtenues nous permet de proposer plusieurs mecanismes de protection, communs et specifiques, mis en oeuvre par les cellules souches de l'epiderme en reponse aux stress radiatifs UVB et gamma
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Additional details
Additional titles
- Original title (French)
- Etude de la reponse des cellules souches epidermiques aux stress genotoxiques radiatifs
Identifiers
Publishing Information
- Imprint Pagination
- 296 p.
- Report number
- FRCEA-TH--6623
INIS
- Country of Publication
- France
- Country of Input or Organization
- France
- INIS RN
- 47013487
- Subject category
- S63: RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS;
- Resource subtype / Literary indicator
- Thesis
- Descriptors DEI
- DNA DAMAGES; DNA REPAIR; EPIDERMIS; GAMMA RADIATION; IONIZING RADIATIONS; KERATIN; STEM CELLS; ULTRAVIOLET RADIATION
- Descriptors DEC
- ANIMAL CELLS; ANIMAL TISSUES; BIOLOGICAL RECOVERY; BIOLOGICAL REPAIR; BODY; ELECTROMAGNETIC RADIATION; EPITHELIUM; IONIZING RADIATIONS; ORGANIC COMPOUNDS; ORGANS; PROTEINS; RADIATIONS; REPAIR; SCLEROPROTEINS; SKIN; SOMATIC CELLS
Optional Information
- Notes
- 379 refs.; Available from the INIS Liaison Officer for France, see the 'INIS contacts' section of the INIS-NKM website for current contact and E-mail addresses: http://www.iaea.org/inis/Contacts/; Also available from Service Commun de la Documentation Direction Domaine universitaire de Paris-Sud Bat 407 Rue du Doyen-Poitou 91405 ORSAY cedex (France)