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

Abstract

Mesenchymal stem cells (MSC) have been shown to improve wound healing and sup-press 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.

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019

“…MSCs have been studied as a promising candidate to treat certain inflammatory conditions and immunologic diseases based on their well-characterized immunomodulatory effects. The immunomodulatory activities are thought to include the following: 1) inhibition of the proliferation and function of T cells, B cells, dendritic cells, and natural killer cells; 2) monocyte polarization to anti-inflammatory M2 macrophages; and 3) production of IL-10 and decreased production of TNF-α and IL-12 ( 28 , 29 ). Indeed, PLX-PAD, a MSC-like product, has been shown to have such immunomodulatory properties ( 19 ).…”

Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome

“…13,14 The immunomodulatory activities are thought to include (a) inhibition of the proliferation and function of T cells, B cells, dendritic cells, and natural killer cells; (b) monocyte polarization to anti-inflammatory M2 macrophages; and (c) production of IL-10 and decreased production of TNF-α and IL-12. [15][16][17] In addition, MSCs have powerful antifibrotic effects and may alleviate lung fibrosis. 18,19 An urgent question is whether large-scale clinical trials and compassionate use of MSC therapy should be instituted to treat COVID-19-induced ARDS.…”

Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use

“…Moreover, MSCs exhibit antimicrobial activity through the secretion of antimicrobial peptides (AMPs), such as cathelicidin peptide LL-37, hepcidin, β-defensin 2, lipocalin 2, and Hepcidin [71,72].These AMPs act in destroying bacterias by either altering the integrity of the microbial membrane or by encouraging the release of proinflammatory cytokines which in turn favors the recruitment of immune cells [71]. Therefore, there is an over-stimulation of the immune cells, as the formation of neutrophil extracellular traps (NETs) by neutrophils [71].…”