Antimicrobial activity of mesenchymal stem cells against Staphylococcus aureus

Abstract

Introduction: There have been limited advances in the treatment of bone and joint infections, which currently involves a combination of surgery and antibiotic administration. There is a timely need in orthopedics to develop more effective and less invasive forms of antimicrobial prophylaxis and treatment. The antibacterial effect of adult tissue-derived mesenchymal stem cells (MSCs) has recently been investigated against Escherichia coli and Staphylococcus aureus. The main mechanism of action is postulated to be via MSC production of the cationic antimicrobial peptide, LL-37. Methods: This study examines the antimicrobial activity of adipose-derived human MSCs (ASCs) on S. aureus, specifically examining the role of LL-37 and regulation of its expression. Bacteria colony-forming unit (CFU) assay was used to assess antimicrobial activity. Results: Our results showed that the ASC-conditioned medium significantly inhibited the growth of S. aureus under standard culture conditions with or without the continued presence of ASCs. Also, the treatment of ASCs with 1,25dihydroxy vitamin D 3 elevated LL-37 expression and enhanced their antimicrobial activity. In support, treatment with the vitamin D receptor inhibitor, GW0742, blocked the antimicrobial activity of ASCs. Conclusion: Our findings clearly demonstrate the antimicrobial activity of adult ASCs against S. aureus and implicate a key regulatory role for vitamin D. Further testing in in vivo models is being pursued to assess the potential application of ASCs as a biocompatible, adjunct treatment for musculoskeletal infections.

Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine

“…Thus, they might act directly through the secretion of antimicrobial peptides, which are evolutionarily conserved small effector molecules (10–150 amino acids) found in organisms ranging from prokaryotes to humans [ 75 ]. These peptides include cathelicidin, defensins, cystatin C, elafin, and lipocalin 2 [ 76 ]. They mediate antimicrobial cell killing, which occurs by disrupting membrane integrity; inhibiting protein, DNA, or RNA synthesis; and interacting with certain intracellular targets [ 77 ].…”

Immune-Based Anti-Staphylococcal Therapeutic Approaches

“…Exploration of human stem cells has also shown the potential of these cells as anti-staphylococcal therapeutics. Studies have showed that the adipose-derived human mesenchymal stem cells (MSC) significantly inhibited the growth of S. aureus under standard culture conditions with or without the continued presence of adipose stem cells (ASCs) through MSC production of the cationic antimicrobial peptide, LL-37 [ 61 ]. In addition, treatment of ASCs with 1,25(OH)2 vitamin D3 elevated LL-37 expression and enhanced their antimicrobial activity, whereas a vitamin D receptor inhibitor, GW0742, blocked the antimicrobial activity of MSCs [ 61 ].…”

“…Studies have showed that the adipose-derived human mesenchymal stem cells (MSC) significantly inhibited the growth of S. aureus under standard culture conditions with or without the continued presence of adipose stem cells (ASCs) through MSC production of the cationic antimicrobial peptide, LL-37 [ 61 ]. In addition, treatment of ASCs with 1,25(OH)2 vitamin D3 elevated LL-37 expression and enhanced their antimicrobial activity, whereas a vitamin D receptor inhibitor, GW0742, blocked the antimicrobial activity of MSCs [ 61 ]. When introduced into rats, bone marrow-derived MSCs enhanced bacterial clearance, suppressed the expression of cytokines and chemokines and promoted healing of the wound, in comparison to the fibroblast control groups [ 62 ].…”

Mesenchymal Stromal Cells as Potential Antimicrobial for Veterinary Use—A Comprehensive Review

“…A number of preconditioning methods have been employed over the years including hypoxia, serum deprivation, and exposure to antagonistic substances to improve MSCs' ability to differentiate or modulate immune cells. Conditions promoting antimicrobial activity are being examined with exposure to cytokines, target bacteria, bacterial components, vitamins, and antibiotics improving both direct and indirect antimicrobial effects (Gupta et al, 2012;Guerra et al, 2017;Johnson et al, 2017;Cahuascanco et al, 2019;Yagi et al, 2020).…”

“…Investigators identified LL-37 activity as crucial to MSC antimicrobial activity in vitro as well as in an in vivo mouse model using human MSCs (Krasnodembskaya et al, 2010). Yagi et al (2020) further found LL-37 activity from adipose-derived MSCs was dependent on 1,25-dihydroxy vitamin D3. 1,25-dihydroxy vitamin D3 supplementation enhanced LL-37 production relative to MSCs under standard culture conditions, whereas treatment with a vitamin D receptor inhibitor nullified the antibacterial response.…”