Activated Mesenchymal Stromal Cell Therapy for Treatment of Multi-Drug Resistant Bacterial Infections in Dogs

Abstract

New and creative approaches are required to treat chronic infections caused by increasingly drug-resistant strains of bacteria. One strategy is the use of cellular therapy employing mesenchymal stromal cells (MSC) to kill bacteria directly and to also activate effective host immunity to infection. We demonstrated previously that activated MSC delivered systemically could be used effectively together with antibiotic therapy to clear chronic biofilm infections in rodent models. Therefore, we sought in the current studies to gain new insights into the antimicrobial properties of activated canine MSC and to evaluate their effectiveness as a novel cellular therapy for treatment of naturally-occurring drug resistant infections in dogs. These studies revealed that canine MSC produce and secrete antimicrobial peptides that synergize with most classes of common antibiotics to trigger rapid bactericidal activity. In addition, activated canine MSC migrated more efficiently to inflammatory stimuli, and secreted factors associated with wound healing and fibroblast proliferation and recruitment of activated neutrophils. Macrophages incubated with conditioned medium from activated MSC developed significantly enhanced bactericidal activity. Clinical studies in dogs with chronic multidrug resistant infections treated by repeated i.v. delivery of activated, allogeneic MSC demonstrated significant clinical benefit, including infection clearance and healing of infected tissues. Taken together, the results of these studies provide new insights into antimicrobial activity of canine MSC, and their potential clinical utility for management of chronic, drug-resistant infections.

Surgical limb‐sparing in veterinary medicine: A review of existing techniques in dogs

“…Although a single care report, activated mesenchymal stromal cell therapy led to the successful treatment of dog with a limb spare with a multidrug resistant bacterial infection. 94 As previously mentioned, dogs with an infection after limb sparing have on average a longer survival time. 74,76,77,95 This finding has also been reported in people with deep infections after surgical limb sparing for osteosarcoma.…”

Surgical limb‐sparing in veterinary medicine: A review of existing techniques in dogs

“…Although a single care report, activated mesenchymal stromal cell therapy led to the successful treatment of dog with a limb spare with a multidrug resistant bacterial infection. 94 As previously mentioned, dogs with an infection after limb sparing have on average a longer survival time. 74,76,77,95 This finding has also been reported in people with deep infections after surgical limb sparing for osteosarcoma.…”

Nonantibiotic Treatment of Clinical Multidrug‐Resistant Bacterial Isolates Using Chitosan Nanoparticles as a Carrier for the Supernatant of Mesenchymal Stem Cells

“…The innovative use of MSCs as a host‐isolated antibacterial agent against E. coli and S. aureus has been investigated in various studies. The primary mechanism of antimicrobial activity of MSCs is the secretion of LL‐37 as a cationic antimicrobial peptide [ 18 , 19 ]. In another research carried out by Chow et al, the bactericidal potential of activated MSCs against MDR isolates was investigated.…”

“…Studies have revealed that the simultaneous use of MSCs with the most common antibiotic classes synergistically increases their antibacterial activities. However, few studies have been performed to investigate the therapeutic effect of MSCs along with other components on drug‐resistant chronic infections to inhibit bacterial growth [ 18 ].…”

“…Other research has highlighted that MSCs combined with major antibiotic classes, including aminoglycosides, cephalosporins, vancomycin, fluoroquinolones, and chloramphenicol, substantially enhance bactericidal activity against Staphylococcus species and Escherichia coli [ 18 ].…”

“…In fact, various complementary mechanisms are probably involved in the antimicrobial activities of MSCs against MDR bacteria, including the secretion of local antimicrobial peptides (direct effect) and systemic stimulation of host innate immunity (indirect effect) [ 18 ]. The present study findings highlight the potential of MSCs CM–CS NPs as a growth inhibitor against MDR bacteria.…”

Surgical limb‐sparing in veterinary medicine: A review of existing techniques in dogs

“…Although a single care report, activated mesenchymal stromal cell therapy led to the successful treatment of dog with a limb spare with a multidrug resistant bacterial infection. 94 As previously mentioned, dogs with an infection after limb sparing have on average a longer survival time. 74,76,77,95 This finding has also been reported in people with deep infections after surgical limb sparing for osteosarcoma.…”

Nonantibiotic Treatment of Clinical Multidrug‐Resistant Bacterial Isolates Using Chitosan Nanoparticles as a Carrier for the Supernatant of Mesenchymal Stem Cells

“…The innovative use of MSCs as a host‐isolated antibacterial agent against E. coli and S. aureus has been investigated in various studies. The primary mechanism of antimicrobial activity of MSCs is the secretion of LL‐37 as a cationic antimicrobial peptide [ 18 , 19 ]. In another research carried out by Chow et al, the bactericidal potential of activated MSCs against MDR isolates was investigated.…”

“…Studies have revealed that the simultaneous use of MSCs with the most common antibiotic classes synergistically increases their antibacterial activities. However, few studies have been performed to investigate the therapeutic effect of MSCs along with other components on drug‐resistant chronic infections to inhibit bacterial growth [ 18 ].…”

“…Other research has highlighted that MSCs combined with major antibiotic classes, including aminoglycosides, cephalosporins, vancomycin, fluoroquinolones, and chloramphenicol, substantially enhance bactericidal activity against Staphylococcus species and Escherichia coli [ 18 ].…”

“…In fact, various complementary mechanisms are probably involved in the antimicrobial activities of MSCs against MDR bacteria, including the secretion of local antimicrobial peptides (direct effect) and systemic stimulation of host innate immunity (indirect effect) [ 18 ]. The present study findings highlight the potential of MSCs CM–CS NPs as a growth inhibitor against MDR bacteria.…”

Surgical limb‐sparing in veterinary medicine: A review of existing techniques in dogs

“…Although a single care report, activated mesenchymal stromal cell therapy led to the successful treatment of dog with a limb spare with a multidrug resistant bacterial infection. 94 As previously mentioned, dogs with an infection after limb sparing have on average a longer survival time. 74,76,77,95 This finding has also been reported in people with deep infections after surgical limb sparing for osteosarcoma.…”

Nonantibiotic Treatment of Clinical Multidrug‐Resistant Bacterial Isolates Using Chitosan Nanoparticles as a Carrier for the Supernatant of Mesenchymal Stem Cells

“…The innovative use of MSCs as a host‐isolated antibacterial agent against E. coli and S. aureus has been investigated in various studies. The primary mechanism of antimicrobial activity of MSCs is the secretion of LL‐37 as a cationic antimicrobial peptide [ 18 , 19 ]. In another research carried out by Chow et al, the bactericidal potential of activated MSCs against MDR isolates was investigated.…”

“…Studies have revealed that the simultaneous use of MSCs with the most common antibiotic classes synergistically increases their antibacterial activities. However, few studies have been performed to investigate the therapeutic effect of MSCs along with other components on drug‐resistant chronic infections to inhibit bacterial growth [ 18 ].…”

“…Other research has highlighted that MSCs combined with major antibiotic classes, including aminoglycosides, cephalosporins, vancomycin, fluoroquinolones, and chloramphenicol, substantially enhance bactericidal activity against Staphylococcus species and Escherichia coli [ 18 ].…”

“…In fact, various complementary mechanisms are probably involved in the antimicrobial activities of MSCs against MDR bacteria, including the secretion of local antimicrobial peptides (direct effect) and systemic stimulation of host innate immunity (indirect effect) [ 18 ]. The present study findings highlight the potential of MSCs CM–CS NPs as a growth inhibitor against MDR bacteria.…”