HGF, MMPs and TGF-β1 contribute to INTERLEUKIN-1β primed mesenchymal stromal cells effect on wound healing and epidermal substitute engraftment

Abstract

Background & Aim In spite of several research advances in the field of skin tissue engineering and regenerative medicine, little progress has been made in the management of major burns. Since the 1980s, deep and extensive skin wounds and burns are treated with autologous Split-Thickness Skin Grafts, or Cultured Epidermal Autografts (CEAs) when donor sites are limited. While CEAs allow patient survival in most critical cases, poor engraftment rates and reduced skin functionality limit the clinical use of CEAs. In the past few decades, Mesenchymal Stromal Cells (MSCs) therapy has emerged as a new strategy to promote wound healing through anti-inflammatory, anti-microbial, 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 priming cues. Thus, the present work aims to assess the benefit and mechanism of action of Interleukin-1β (IL-1β) primed MSCs or their secretory products on wound healing and epidermal substitute engraftment. Methods, Results & Conclusion Naive and IL-1β-primed MSCs or their Conditioned Media (CM) were evaluated in in vitro models of migration, inflammation and Dermal-Epidermal Junction (DEJ) formation, and in an in vivo skin excisional and epidermal substitute grafting mouse model. We showed that the IL-1β priming potentiates the MSC efficacy through the reduction of inflammation and the promotion of cell migration, DEJ remodeling and epidermal substitute engraftment. These positive effects were partly mediated by MSC paracrine secretions which targeted downstream p38MAPK, SMAD and MMP signalings. Among priming-induced secreted factors, MMP-1, MMP-9, HGF and TGF-β1 were found to play key roles in the resolution of wound healing. 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.