Mesenchymal Stromal Cell-Secreted CCL2 Promotes Antibacterial Defense Mechanisms Through Increased Antimicrobial Peptide Expression in Keratinocytes

Abstract

Abstract Mesenchymal stromal cells (MSCs) from both humans and horses, which represent a clinically relevant translation animal model for human cutaneous wound healing, were recently found to possess antimicrobial properties against planktonic bacteria, and in the case of equine MSCs, also against biofilms. This, together with previous findings that human and equine MSCs promote angiogenesis and wound healing, makes these cells an attractive approach to treat infected cutaneous wounds in both species. The anti-biofilm activities of equine MSC, via secretion of cysteine proteases, have only been demonstrated in vitro, thus lacking information about in vivo relevance. Moreover, the effects of the equine MSC secretome on resident skin cells have not yet been explored. The goals of this study were to (a) test the efficacy of the MSC secretome in a physiologically relevant ex vivo equine skin biofilm explant model and (b) explore the impact of the MSC secretome on the antimicrobial defense mechanisms of resident skin cells. Our salient findings were that secreted factors from equine MSCs significantly decreased viability of methicillin-resistant Staphylococcus aureus bacteria in mature biofilms in this novel skin biofilm explant model. Moreover, we demonstrated that equine MSCs secrete CCL2 that increases the antimicrobial activity of equine keratinocytes by stimulating expression of antimicrobial peptides. Collectively, these data contribute to our understanding of the MSC secretome's antimicrobial properties, both directly by killing bacteria and indirectly by stimulating immune responses of surrounding resident skin cells, thus further supporting the value of MSC secretome-based treatments for infected wounds.