164 Molecular characterization of the response to haploidentical mesenchymal stem cells treatment in recessive dystrophic epidermolysis bullosa patients

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable rare skin fragility disorder characterized by deficient dermo-epidermal adhesion due to mutations in the gene encoding collagen VII (COL7A1). Patients with RDEB suffer chronic wounds and inflammation, exacerbated by pruritus, and ultimately trigger fibrosis and highly aggressive squamous cell carcinoma. Although classified as a skin disease, its symptoms affect multiple internal organs and tissues, which underscores the need for systemic treatment; allogenic mesenchymal stem cells (MSCs) derived from bone marrow have previously shown some benefit in patients with RDEB. The goal of this work is to understand the mechanisms by which MSCs exert their therapeutic effect in the unique context provided by a clinical trial (NCT04153630) in addition to characterization of the baseline profile of the recruited RDEB patients. Comparative transcriptomic analysis (RNA-Seq) of skin biopsies from 8 patients, before and after the MSC infusion, revealed differential expression of 41 genes, including some related to key functions such as inflammatory response (FOS, osteopontin) or pruritus (corneodesmosin). An enrichment analysis provided further insight highlighting some biological processes such as barrier function and oxidative stress. Finally, a further interactome network and mechanistic analysis showed that JAK-Stat and FoxO signaling pathways are modulated as a result of the MSC action. These preliminary data might be key for predicting the outcome of patient’s condition, understanding the global and individual response to MSCs and for optimization of treatment, as well as the development of new ones.