​ Nicolas FORTUNEL Principal investigator Phone : +33 (0)1 60 87 34 92 nicolas.fortunel@cea.fr Genopole 2 avenue Gaston Crémieux 91000 EVRY cedex France

The skin is a particularly suitable biological model for studying tissue stem cells in humans, and exploring their therapeutic applications. More generally, access to samples of adult human skin, and the resulting possibility of developing 2D cell models and 3D organoids, make possible studies of physiological processes and pathological dysregulations affecting this organ.

The research conducted by the ER2C team is divided into three areas:​

1 – Molecular determinants of the 'stem cell' character or 'stemness'.

The first area focuses on understanding the fundamental characteristics of epithelial stem and progenitor cells that reside within the interfollicular epidermis and hair follicles. This upstream research area specifically aims to generate knowledge on the molecular determinants of ‘stemness’, as well as to decipher the regulatory networks governing the balance between immaturity and differentiation in these tissue stem cell models. The TGFB1 pathway and associated transcription factors are being studied in particular for their role in controlling stemness and the self-renewal capacity of cutaneous epithelial stem cells. More broadly, this research integrates the conventional coding genome (genes encoding the proteome) and the epigenome (genes producing non-coding transcripts), especially the class of long non-coding RNAs (lncRNAs), whose regulatory functions are attracting increasing interest.

2 – Cultured skin substitutes.​

Fueled by this upstream research, a translational area aims to produce concepts and innovations for the benefit of the cutaneous cell and tissue therapy field. A first line of work focuses on the development of molecular compositions and effectors promoting a pro-'stemness' action, allowing for more effective preservation of epidermal stem cells in the context of bioengineered skin substitute architectures. Their maintenance during the culture process indeed conditions the regenerative potential of the resulting grafts. A second line of work addresses the issue of immune rejection, which limits the applications of allogeneic grafts. The approach explored involves vectoring molecules that promote a tolerogenic signal into skin cells, with the aim of generating grafts with endowed with attenuated immunogenicity.

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3 – Cutaneous radio-pathologies.

A third area of focus concerns the cutaneous consequences of genotoxic stress induced by ionizing radiation (IR), particularly exposure of healthy skin in the context of medical applications (imaging, radiotherapy). A first line of work focuses on the impact of this medical exposome on the integrity and function of epidermal stem and progenitor cells. A second line of work concerns dermal fibroblasts, which are studied for their role as primary effector cells in the development of radiation-induced cutaneous fibrosis. The pathophysiology molecular effectors are studied at the level of the coding genome and the non-coding transcriptome. Candidate targets suitable for the design of corrective approaches are being 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].
• PCR / RT-PCR digital droplets (BioRad).
  

• CEA, Immuno-Hematology Research Unit (SRHI), Saint-Louis Hospital, Paris.
• Grenoble-Alpes University (UGA) – CEA, Interdisciplinary Research Institute of Grenoble (Irig).
• French Defence Central Health Service (SSA) – French Armed-Forces Blood Transfusion Center (CTSA), Percy-Clamart Hospital.
• AP-HP – Hôpital Européen Georges Pompidou, Hematology department.
• University of Southern California – Cedars-Sinai Medical Center – Vascularized Composite Allotransplantion Laboratory, Los Angeles.
• L'Oréal – Advanced Research.