Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies

Abstract

While mesenchymal stem cells (MSCs)-based therapy appears to be promising, there are concerns regarding possible side effects related to the unwanted suppression of antimicrobial immunity leading to an increased risk of infection. Conversely, recent data show that MSCs exert strong antimicrobial effects through indirect and direct mechanisms, partially mediated by the secretion of antimicrobial peptides and proteins (AMPs). In fact, MSCs have been reported to increase bacterial clearance in preclinical models of sepsis, acute respiratory distress syndrome, and cystic fibrosis-related infections. This article reviews the current evidence regarding the direct antimicrobial effector function of MSCs, focusing mainly on the role of MSCs-derived AMPs. The strategies that might modulate the expression and secretion of these AMPs, leading to enhanced antimicrobial effect, are highlighted. Furthermore, studies evaluating the presence of AMPs in the cargo of extracellular vesicles (EVs) are underlined as perspective opportunities to develop new drug delivery tools. The antimicrobial potential of MSCs-derived EVs can also be heightened through cell conditioning and/or drug loading. Finally, improving the pharmacokinetics and delivery, in addition to deciphering the multi-target drug status of AMPs, should synergistically lead to key advances against infections caused by drug-resistant strains.

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

“…Previous studies have determined that the primary mediators of MSC secreted bactericidal activity are AMP . It has also been reported previously that AMP such as LL‐37 can synergize with conventional antibiotics for bacterial killing .…”

“…Expression of AMPs by human MSC has been reported previously . To confirm the expression by the MSC used in our system, we examined expression of the following peptides cathelicidin LL‐37, beta defensin (hBD2), hepcidin, surfactant protein D (SPD), and lipocalin(LcN), using flow cytometry and immunocytochemistry .…”

“…Expression of AMPs by human MSC has been reported previously . To confirm the expression by the MSC used in our system, we examined expression of the following peptides cathelicidin LL‐37, beta defensin (hBD2), hepcidin, surfactant protein D (SPD), and lipocalin(LcN), using flow cytometry and immunocytochemistry . These studies revealed that MSC expressed four of the five AMPs, whereas the expression of surfactant protein D could not be conclusively detected by flow cytometry and only displayed low levels of staining by immunocytology (Figure A,B).…”

“…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.…”

Silk‐Based Antimicrobial Polymers as a New Platform to Design Drug‐Free Materials to Impede Microbial Infections

“…Hep was previously described to have antibacterial activity. This is a natural human host defense peptide known to act as an iron regulatory hormone, and to have a broad spectrum of antimicrobial activity against E. coli , S. epidermidis , S. aureus , and group B streptococci, as well as fungi …”