Antimicrobial Properties of Mesenchymal Stem Cells: Therapeutic Potential for Cystic Fibrosis Infection, and Treatment

Abstract

Cystic fibrosis (CF) is a genetic disease in which the battle between pulmonary infection and inflammation becomes the major cause of morbidity and mortality. We have previously shown that human MSCs (hMSCs) decrease inflammation and infection in the in vivo murine model of CF. The studies in this paper focus on the specificity of the hMSC antimicrobial effectiveness using Pseudomonas aeruginosa (gram negative bacteria) and Staphylococcus aureus (gram positive bacteria). Our studies show that hMSCs secrete bioactive molecules which are antimicrobial in vitro against Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumonia, impacting the rate of bacterial growth and transition into colony forming units regardless of the pathogen. Further, we show that the hMSCs have the capacity to enhance antibiotic sensitivity, improving the capacity to kill bacteria. We present data which suggests that the antimicrobial effectiveness is associated with the capacity to slow bacterial growth and the ability of the hMSCs to secrete the antimicrobial peptide LL-37. Lastly, our studies demonstrate that the tissue origin of the hMSCs (bone marrow or adipose tissue derived), the presence of functional cystic fibrosis transmembrane conductance regulator (CFTR: human, Cftr: mouse) activity, and response to effector cytokines can impact both hMSC phenotype and antimicrobial potency and efficacy. These studies demonstrate, the unique capacity of the hMSCs to manage different pathogens and the significance of their phenotype in both the antimicrobial and antibiotic enhancing activities.

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

“…An in-vivo study on CF lung treated with hMSCs showed significant reduction in the bacterial infection and an increase in the production of antimicrobial peptide LL-37. hMSCs have the potential to increase the efficacy of antibiotics and decrease the bacterial growth by releasing soluble products [197]. In addition to the bronchial epithelial cells, nasal airway epithelial cells, intestinal organoids from intestinal stem cell biopsy, monocytes and macrophages have also been studied for CFTR therapy [198, 199].…”

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

“…On the other hand, current data suggest that MSCs exert strong antimicrobial effects through indirect and direct mechanisms (16–26). Indirectly, across their role in the host immune response against pathogens, especially in the dynamic coordination of the pro- and anti-inflammatory elements of the immune system (22, 27–29) or increasing the activity of phagocytes (18, 21, 25, 30, 31); and directly, by the secretion of antimicrobial peptides and proteins (AMPs) (19, 20, 23, 24, 26), and also by the expression of molecules such as indoleamine 2,3-dioxygenase (IDO) (16) and interleukin (IL)-17 (32). In fact, MSCs have been reportedly responsible of the bacterial clearance in preclinical models of sepsis (17–20, 22, 25), acute respiratory distress syndrome (ARDS) (21, 26), and cystic fibrosis infection (23).…”

“…These molecules have selective activity against a wide range of organisms including bacteria, yeasts, fungi, viruses, and even cancer cells (34). So far, MSCs have been found to constitutively express four AMPs: cathelicidin LL-37 (19, 23), human β-defensin-2 (hBD-2) (24), hepcidin (20), and lipocalin-2 (Lcn2) (26), which can be further modulated during infection and inflammation. In fact, it has been demonstrated that, in MSCs, a bacterial preconditioning induces an upregulation of LL-37, hBD-2, and hepcidin (19, 20, 24), while their preconditioning with inflammatory stimuli evoke increasing levels of LL-37 and Lcn2 (23, 26).…”

“…So far, MSCs have been found to constitutively express four AMPs: cathelicidin LL-37 (19, 23), human β-defensin-2 (hBD-2) (24), hepcidin (20), and lipocalin-2 (Lcn2) (26), which can be further modulated during infection and inflammation. In fact, it has been demonstrated that, in MSCs, a bacterial preconditioning induces an upregulation of LL-37, hBD-2, and hepcidin (19, 20, 24), while their preconditioning with inflammatory stimuli evoke increasing levels of LL-37 and Lcn2 (23, 26). In different preclinical models, MSCs-derived AMPs have demonstrated to be part of the bacterial clearance effect observed with MSCs treatment, revealing that MSCs can directly enhance the innate immune response to bacterial infection (19, 20, 23, 24, 26).…”

Role of Mesenchymal Multipotent Stromal Cells in Remodeling of Bone Defects

“…Транзиторное воздействие TNFα, ЛПС или других лигандов TLR увеличивает остеогенез и зависит от дозы, времени и периода воздействия стимулов [13]. Однако, воздействие хронической воспалитель-ной среды вызывает активацию остеокластов и нарушение остеогенеза МСК и изменяет ба-ланс ремоделирования кости в сторону остеоли-тического процесса [54].…”