Abstract

Mesenchymal stem cells (MSC) have been shown to improve wound healing and suppress inflammatory immune responses. Newer research also indicates that MSC exhibit antimicrobial activity, although the mechanisms underlying this activity have not been fully elucidated. Therefore, we conducted in vitro and in vivo studies to examine the ability of resting and activated MSC to kill bacteria, including multidrug resistant strains. We investigated direct bacterial killing mechanisms and the interaction of MSC with host innate immune responses to infection. In addition, the activity of MSC against chronic bacterial infections was investigated in a mouse biofilm infection model. We found that MSC exhibited high levels of spontaneous direct bactericidal activity in vitro. Moreover, soluble factors secreted by MSC inhibited Staphylococcus aureus biofilm formation in vitro and disrupted the growth of established biofilms. Secreted factors from MSC also elicited synergistic killing of drug‐resistant bacteria when combined with several major classes of antibiotics. Other studies demonstrated interactions of activated MSC with host innate immune responses, including triggering of neutrophil extracellular trap formation and increased phagocytosis of bacteria. Finally, activated MSC administered systemically to mice with established S. aureus biofilm infections significantly reduced bacterial numbers at the wound site and improved wound healing when combined with antibiotic therapy. These results indicate that MSC generate multiple direct and indirect, immunologically mediated antimicrobial activities that combine to help eliminate chronic bacterial infections when the cells are administered therapeutically.

Highlights

  • Lyndah Chow and Valerie Johnson contributed to this study.The increasing incidence of antibiotic resistant bacterial infections has prompted a search for more effective therapies, including alternatives to STEM CELLS Transl Med. 2020;9:235–249.wileyonlinelibrary.com/journal/sct[3 ] CHOW ET AL.conventional antibiotics.[1]

  • We found that activated mesenchymal stem cell (MSC) delivered systemically demonstrated strong antibacterial activity and elicited resolution of wound infection when combined with antibiotic therapy

  • We found that when S. aureus and E. coli were incubated with MSC Conditioned medium (CM), strong bactericidal activity was detected, and caused a decrease of greater than 2log CFU/mL of bacterial growth (Figure 1A)

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Summary

| INTRODUCTION

Lyndah Chow and Valerie Johnson contributed to this study. The increasing incidence of antibiotic resistant bacterial infections has prompted a search for more effective therapies, including alternatives to. In the same study we 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.[4] Based on these compelling data from realistic animal models of chronic bacterial biofilm infections, we have investigated in greater detail the mechanisms by which human MSC may control or eradicate bacterial infections, for the ultimate goal of translating MSC therapy to humans with chronic infections. A mouse chronic implant infection model was used to assess the effectiveness of activated human MSC The results of these studies provide insights into the multiple mechanisms by which MSC may be used as adjunctive therapy along with antibiotics for treating highly drugresistant infections in relatively inaccessible sites such as implant infections. This information will help guide the design of clinical trials to investigate MSC therapy as a new tool for managing drug resistant infections

| MATERIALS AND METHODS
| RESULTS
Findings
| DISCUSSION
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