Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases

Abstract

There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.

Keywords: antimicrobial; cell therapy; clinical trials; host-directed therapy; immunomodulation; immunotherapy; infectious diseases; mesenchymal stromal cells; pathogens.

FIG 1

Direct antimicrobial activity of MSCs through secretion of antimicrobial peptides. Activated MSCs secrete antimicrobial peptides which have a range of bactericidal and bacteriostatic effects. LL-37 permeabilizes the bacterial cell walls and neutralizes endotoxins. β-Defensin also targets the bacterial cell wall, as well as genomic DNA. Hepcidin binds the iron transporter ferroportin and sequesters iron inside host cells. Lipocalin-2 binds to bacterial siderophores to reduce their access to iron.

FIG 2

MSC modulation of monocytes and macrophages. MSCs home to the site of infection and exert a range of immunomodulatory effects on macrophages to enhance their function, including (i) promoting monocyte recruitment and differentiation into macrophages via CCL2 secretion, (ii) increasing phagocytosis and oxidative burst via KGF and GM-CSF, (iii) enhancing macrophage degradation of bacteria via PGE2 and IDO signaling, (iv) promoting macrophage bioenergetics and inhibition of apoptosis by transfer of mitochondria, (v) enhancing autophagy of cytosolic bacteria by TGF-β, and (vi) supporting macrophage repair of injured tissue via IL-10.

FIG 3

MSC modulation of other immune cells. MSCs modulate innate and adaptive immune cells to enhance pathogen clearance and reduce host tissue damage. MSCs increase levels of GM-CSF in neutrophils via IL-6 and IL-17 signaling, which enhances phagocytosis and bacterial clearance. MSCs transfer mitochondria to CD4⁺ and CD8⁺ lymphocytes which augments their bioenergetics and improves long-term immune memory. MSCs protect host tissue by inhibiting release of MPO from neutrophils and proteases from NK cells. MSCs suppress excessive inflammation by modulating DCs and regulatory lymphocytes via numerous soluble mediators, including IDO, PGE2, and TSG-6.