Anti-inflammatory effect of interleukin-6 highly enriched in secretome of two clinically relevant sources of mesenchymal stromal cells.

Despite several advances in the field of regenerative medicine, clinical management of extensive skin wounds or burns remains a major therapeutic issue. During the past few years, Mesenchymal Stromal Cells (MSCs) have emerged as a novel therapeutic tool to promote tissue repair through their anti-inflammatory, pro-trophic and pro-remodeling effects. They exert their biological activity mainly via the secretion of soluble bioactive molecules such as cytokines, growth factors, proteins and microRNAs which can be encapsulated within extracellular vesicles (EV). The recent discovery of their high plasticity to external stimuli has fostered the development of new targeted therapies known as priming strategies, to enhance their potential. Our team recently showed that Interleukin-1ß (IL-1ß)-primed gingival MSCs promote wound healing and epidermal engraftment in vitro, and in vivo through their secreted products that contain extracellular vesicles. In the present work, we investigated whether two common sources of MSCs, gingiva and bone marrow, could respond similarly to IL-1ß to favor pro-healing capabilities of their secretome. We showed that both primed-MSC sources, or their related secreted products, are able to reduce inflammation in LPS-challenged human monocytic THP-1 cell line. IL-1ß priming enhanced MSC secretion of wound healing-related growth factors, cytokines and miRNAs in both sources. Among them, interleukin 6 was shown to be involved in the anti-inflammatory effect of MSC secreted products. Overall, these results underline the pro-healing properties of both MSC sources and their secretome upon IL-1ß priming and their potential to improve the current medical treatment of severe wounds.

Development of extracellular vesicle-based medicinal products: A position paper of the group "Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France".

Extracellular vesicles (EV) are emergent therapeutic effectors that have reached clinical trial investigation. To translate EV-based therapeutic to clinic, the challenge is to demonstrate quality, safety, and efficacy, as required for any medicinal product. EV research translation into medicinal products is an exciting and challenging perspective. Recent papers, provide important guidance on regulatory aspects of pharmaceutical development, defining EVs for therapeutic applications and critical considerations for the development of potency tests. In addition, the ISEV Task Force on Regulatory Affairs and Clinical Use of EV-based Therapeutics as well as the Exosomes Committee from the ISCT are expected to contribute in an active way to the development of EV-based medicinal products by providing update on the scientific progress in EVs field, information to patients and expert resource network for regulatory bodies. The contribution of our work group "Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France", created in 2020, can be positioned in complement to all these important initiatives. Based on complementary scientific, technical, and medical expertise, we provide EV-specific recommendations for manufacturing, quality control, analytics, non-clinical development, and clinical trials, according to current European legislation. We especially focus on early phase clinical trials concerning immediate needs in the field. The main contents of the investigational medicinal product dossier, marketing authorization applications, and critical guideline information are outlined for the transition from research to clinical development and ultimate market authorization.

IL-1ß-Primed Mesenchymal Stromal Cells Improve Epidermal Substitute Engraftment and Wound Healing via Matrix Metalloproteinases and Transforming Growth Factor-ß1.

Since the 1980s, deep and extensive skin wounds and burns are treated with autologous split-thickness skin grafts, or cultured epidermal autografts, when donor sites are limited. However, the clinical use of cultured epidermal autografts often remains unsatisfactory because of poor engraftment rates, altered wound healing, and reduced skin functionality. In the past few decades, mesenchymal stromal cells (MSCs) have raised much attention because of their anti-inflammatory, protrophic, and pro-remodeling capacities. More specifically, gingival MSCs have been shown to possess enhanced wound healing properties compared with other tissue sources. Growing evidence also indicates that MSC priming could potentiate therapeutic effects in diverse in vitro and in vivo models of skin trauma. In this study, we found that IL-1ß-primed gingival MSCs promoted cell migration, dermal-epidermal junction formation, and inflammation reduction in vitro, as well as improved epidermal substitute engraftment in vivo. IL-1ß-primed gingival MSCs had different secretory profiles from naive gingival MSCs, characterized by an overexpression of transforming growth factor-ß and matrix metalloproteinase (MMP) pathway agonists. Eventually, MMP-1, MMP-9, and transforming growth factor-ß1 appeared to be critically involved in IL-1ß-primed gingival MSC mechanisms of action.