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.
Highlights
In other studies we have observed that MSC-secreted factors can reduce high level antibiotic resistance in bacterial strains with multi-drug resistance (Johnson V, manuscript in preparation). These findings suggest that activated MSC therapy would be useful in the management of deep-seated infections with highly drug-resistant strains of bacteria, where treatment options other than antibiotic therapy may not exist
The apparent beneficial effect from MSC administration was observed in wounds in diverse locations and with diverse, highly drug-resistant strains of bacteria. These results suggest that systemic administration of activated, allogeneic MSC may be a viable option for the treatment of chronically infected wounds in other species such as humans
Injected activated MSC migrated to the site of wound infection, where they stimulated bacterial killing by secreting antimicrobial peptides and activating host innate immune defenses
Summary
Bacteria were propagated in LB medium (BD Falcon) and utilized to coat mesh implanted material during the log phase of growth. Mice used in these studies included [8,9,10,11,12] week old CD-1 mice, male and females, and were purchased from Charles River Laboratories. Adipose tissues from transgenic mice expressing GFP under the ubiquitin promoter were kindly provided by Dr William Janssen, National Jewish Hospital, Denver, CO41. CCR2-gfp reporter mice (on the C57Bl/6 background) were provided by Dr Eric Pamer (Memorial Sloan Kettering, NY)[42].
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