Interest of interleukin-1β priming on various sources of MSC for wound healing: role of interleukin-6, a MSC secreted factor

Abstract

Background & Aim Deep and extensive skin wounds and burns are treated with autologous Split-Thickness Skin Grafts, with a possible combination of adjuvant therapy, or grafted with Cultured Epidermal Autografts (CEAs) when donor sites are limited. Despite many years of use and the allowing of patient survival, CEA still fail to provide satisfactory clinical outcomes due to poor engraftment rates and reduced skin functionality. In the past few decades, Mesenchymal Stromal Cells (MSCs) therapy have been proposed as a novel therapeutic tool to promote wound healing through anti-inflammatory, pro-trophic and pro-remodeling effects. MSCs are also able to interact with their environment and modify their secretory profile depending on cellular, molecular or physical environment. Our team recently shown that, IL-1β-primed gingival MSCs promoted wound healing in vitro, and in vivo through the secretion of a mix of secreted products and extracellular vesicles. Paracrine mechanism involving MMPs and TGF-βs signaling has been shown to be implicated in MSC primed effect on wound healing. Preliminary results also indicated that IL-6 could also been involved. Therefore, in the present work, we investigated whether other source of MSC could respond similarly to Interleukin 1β to favor wound healing through the secretion of extracellular vesicles and secreted products. Methods, Results & Conclusion Naive and IL-1β-primed MSCs from gingival or bone marrow sources were evaluated in in vitro models of migration, inflammation and Dermal-Epidermal Junction (DEJ) formation. Extracellular vesicles and IL-6 expression were analyzed by NTA and ELISA respectively in the Conditioned Media (CM) of MSC culture. To investigate the mechanism of action of IL-6 in particular, we used human recombinant IL-6 at the concentration found in IL-CM by ELISA and specific blocking antibody in our different in vitro models. Preliminary results indicated that both MSC sources responds similarly to Interleukin-1β priming and have been shown to promote skin cell migration, favor extracellular matrix deposition and reduce inflammation. In vivo studies will be performed to confirm the results observed in vitro. Overall, these results underline the benefit of the IL-1β priming strategy in the treatment of severe skin defects using MSC and epidermal substitute. We hope that this approach could soon improve the current medical treatment of full-thickness burn wounds.