The François Jacob Institute of Biology brings together five departments and three services
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The skin provides a suitable biological model for studying the stem cells of adult organs and tissues in humans. Indeed, several reservoirs of stem cells are hosted within skin, including epithelial stem cells within the epidermal tissue. Our laboratory, the LGRK, investigates the intrinsic properties and the regenerative capacity of skin stem cells, as well as the dialogues taking place within their cutaneous environment. Exposure to ionizing radiation is studied as a model for exploring skin disturbances induced by the exposome.
The research carried out by the LGRK on human skin focuses on three areas:
1 – Molecular determinants of the 'stem cell' character or 'stemness'.
This upstream research axis focuses on knowledge of the fundamental characteristics of the epithelial stem cells and progenitors present within the interfollicular epidermis and the hair follicle. Points of interest include the search for phenotypic criteria associated with the 'stem cell' character, as well as the deciphering of the regulatory networks of the 'immaturity versus differentiation' balance. The TGFB1 pathway and associated transcription factors are particularly studied for their involvement in the control of stemness. More generally, this research integrates the conventional coding genome (genes coding the proteome), and the epigenome (genes producing non-coding transcripts), in particular the class of long non-coding RNAs (lncRNAs).
2 – Cultured skin substitutes.
This translational axis aims to provide concepts and innovations for the benefit of the field of cutaneous cell and tissue therapies. A first line of work concerns the development of effectors promoting a pro-stemness action, thus allowing a more effective preservation of epidermal stem cells ex vivo, in the context of bioengineering architectures of skin substitutes. The targeted gain concerns the quality of regeneration. A second line of work concerns the problem of immune rejection, which restricts the fields of use of allogeneic grafts. The approach explored consists of vectorizing molecules that promote a tolerogenic signal in skin cells, with a view to generating grafts with attenuated immunogenicity.
On this axis, and within the framework of the 'Priority Research Programs and Equipment' (PEPR) 'Biotherapies - Bioproduction', the LGRK is the coordinator of a targeted program on skin cell and tissue therapies: acronym 'Bioengineered Skin France'.
3 – Cutaneous radio-pathologies.
This axis focuses on the cutaneous consequences of genotoxic stresses induced by ionizing radiation (IR), in particular exposure of healthy skin in the context of medical applications (imaging, radiotherapy). A first aspect studied is the impact of this medical exposome on the integrity and functions of epidermal stem cells and progenitors. One aspect of interest concerns dermal fibroblasts, studied for their status as primary effector cells in the development of radiation-induced skin fibrosis. The molecular effectors of physiopathology are studied at the level of the coding genome and the non-coding transcriptome. Candidate targets for the design of corrective approaches are sought.
Primary human skin cells (clonal cultures, long-term cultures, 3D skin organoids).
Flow cytometry (MoFlo ASTRIOS cell sorter, NovoCyte analyzer) [CEA-Genopole platform].
Experimental irradiation (Faxitron Multi Rad 350 X-ray generator) [CEA-Genopole platform].
Transcriptome microarrays (Affymetrix Clariom D); digital droplet PCR / RT-PCR (BioRad).
Coutier J, Auvré F, Lemaître G, Lataillade J-J, Deleuze J-F, Roméo PH, Martin MT, Fortunel NO. MXD4/MAD4 regulates human keratinocyte precursor fate. J Invest Dermatol. 2023 Jan;143(1):105-114.e12. PMID: 36007550 - DOI: 10.1016/j.jid.2022.07.020 Full-text: https://www.jidonline.org/article/S0022-202X(22)01778-X/fulltextxx
Mestrallet G, Auvré F, Schenowitz C, Carosella ED, LeMaoult J, Martin MT, Rouas-Freiss N, Fortunel NO. Human keratinocytes inhibit CD4+ T-cell proliferation through TGFB1 secretion and surface expression of HLA-G1 and PD-L1 immune checkpoints. Cells. 2021 Jun 8; 10(6):1438. PMID: 32998444 - DOI: 10.3390/cells10061438 Full-text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601001/pdf/cells-09-02188.pdf
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 Aug 18; 9(8):1912. PMID: 32824646 - DOI: 10.3390/cells9081912 Full-text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466070/pdf/cells-09-01912.pdf
Fortunel NO, Chadli L, Coutier J, Lemaître G, Auvré F, Domingues S, Bouissou-Cadio E, Vaigot P, Cavallero S, Deleuze JF, Roméo PH, Martin MT. KLF4 inhibition promotes the expansion of keratinocyte precursors from adult human skin and of embryonic-stem-cell-derived keratinocytes. Nature Biomed Eng. 2019 Dec; 3(12):985-997. Epub 2019 Oct 21. PMID: 31636412. (IF 2021: 29.234). - DOI: 10.1038/s41551-019-0464-6 Full-text: https://rdcu.be/b8JPr
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.