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.

Canine polarized macrophages express distinct functional and transcriptomic profiles

“…Macrophage bactericidal activity was assessed as described previously ( 23 , 25 ). Briefly, cultures of S. pseudointermedius were propagated in antibiotic-free macrophage growth medium overnight and grown to log phase prior to addition to macrophage cultures.…”

Salmonella enhances osteogenic differentiation in adipose-derived mesenchymal stem cells

“…MSCs are one host cell type whose role in responding to inflammation and infections means interactions with pathogenic microbes are common occurrence ( Brandau et al, 2014 ; Mezey, Nemeth, 2015 ). In light of their known immunomodulatory role in vivo , MSCs have been investigated as potential therapeutics in instances of drug-resistant pathogens ( Yuan et al, 2014 ; Johnson et al, 2022 ). ( Yuan et al, 2014 ) illustrated the ability of bone marrow-derived MSCs to increase clearance of methicillin-resistant S. aureus (MRSA) in a rat model.…”

Preliminary evaluation of safety and migration of immune activated mesenchymal stromal cells administered by subconjunctival injection for equine recurrent uveitis

“…Given the greater potential for immune response to allogeneic MSCs, it may be even more essential that they are as potent as possible through pIC activation, so they can actualize their benefits prior to being targeted by the host immune system (29). Activated MSCs were utilized in this study to insure that while they have superior immunomodulatory capabilities in vitro (28,29,59) and in other in vivo (56,60) administrations, that they did not induce any intolerable adverse ocular responses.…”

“…In many MSC treatment protocols, multiple administrations of MSCs are recommended, however there is often minimal data to support the timing interval (23,38,56,60). In several studies where MSC tracking has been reported, cell presence is markedly reduced within 14 to 21 days (61, 62) which has led to the paradigm shift in thinking that the proposed benefit of MSC is through recruitment and modulation of immune effector cells rather than differentiation into local cell types (55,63).…”