Activated Mesenchymal Stem Cells Interact with Antibiotics and Host Innate Immune Responses to Control Chronic Bacterial Infections

Abstract

Chronic bacterial infections associated with biofilm formation are often difficult to resolve without extended courses of antibiotic therapy. Mesenchymal stem cells (MSC) exert antibacterial activity in vitro and in acute bacterial infection models, but their activity in chronic infection with biofilm models has not been previously investigated. Therefore, we studied the effects of MSC administration in mouse and dog models of chronic infections associated with biofilms. Mice with chronic Staphylococcus aureus implant infections were treated by i.v. administration of activated or non-activated MSC, with or without antibiotic therapy. The most effective treatment protocol was identified as activated MSC co-administered with antibiotic therapy. Activated MSC were found to accumulate in the wound margins several days after i.v. administration. Macrophages in infected tissues assumed an M2 phenotype, compared to untreated infections which contained predominately M1 macrophages. Bacterial killing by MSC was found to be mediated in part by secretion of cathelicidin and was significantly increased by antibiotics. Studies in pet dogs with spontaneous chronic multi drug-resistant wound infections demonstrated clearance of bacteria and wound healing following repeated i.v. administration of activated allogeneic canine MSC. Thus, systemic therapy with activated MSC may be an effective new, non-antimicrobial approach to treatment of chronic, drug-resistant infections.

Antibacterial activity of human mesenchymal stem cells mediated directly by constitutively secreted factors and indirectly by activation of innate immune effector cells

“…Human MSC have been shown to produce multiple AMPs, including the cathelicidin peptide LL‐37, hepcidin, β‐defensin 2, and lipocalin 2 . MSC‐produced AMPs are thought to be one critical component regulating the ability of MSC administered therapeutically to control or eliminate bacterial infections, as explored in multiple animal models …”

“…Methicillin‐resistant Staphylococcus aureus (MRSA) in particular accounts for high mortality worldwide and is responsible for many chronic implant infections . The use of mesenchymal stem cell (MSC) to treat bacterial infections has received increasing attention in recent years, based on in vitro studies documenting direct bactericidal activity . Thus, it is possible that administration of MSC may be a means of potentiating conventional antibiotic therapy, it is therefore important to elucidate more fully the mechanisms underlying MSC antimicrobial activity, both in vitro and in vivo.…”

“…However, few studies to date have investigated whether MSC can also be used in the treatment of chronic bacterial infections. Notably, our group recently reported that activated murine MSC were effective for the treatment of chronic S. aureus biofilm infection in a mouse implant infection model . In this model, we found that activated MSC delivered systemically demonstrated strong antibacterial activity and elicited resolution of wound infection when combined with antibiotic therapy.…”

“…In this model, we found that activated MSC delivered systemically demonstrated strong antibacterial activity and elicited resolution of wound infection when combined with antibiotic therapy. Importantly, in the same study we also showed that in pet dogs with spontaneous multidrug resistant (MDR) wound infections, systemic administration of activated canine MSC cleared bacterial infection, even when administered to animals with infections that had persisted for months with antibiotic treatment alone …”

Role of Mesenchymal Multipotent Stromal Cells in Remodeling of Bone Defects

“…Современные стратегии создания ткане-инженерных конструкций активно используют МСК для улучшения интеграции имплантатов и предотвращения иммунологического отторже-ния. В доклинических исследованиях показано, что заселение биосовместимых материалов МСК значительно повышает остеокондуктивность и улучшает интеграцию имплантатов [30,38]. Первые клинические испытания скаффолдов, заселенных МСК, подтверждают их эффектив-ность [20].…”