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MSC Secreted Factors – The New Player in the Battle Against Antibiotic-Resistant Bacteria

Review of “The mesenchymal stromal cell secretome impairs methicillin‐resistant Staphylococcus aureus biofilms via cysteine protease activity in the equine model” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Researchers led by Gerlinde R. Van de Walle (Cornell University, Ithaca, NY, USA) have previously demonstrated that mesenchymal stem cell (MSC)-secreted factors promote the angiogenesis and migration of dermal fibroblasts in an equine model [1-3]. The Van de Walle laboratory employs the horse as a physiologically relevant model to study those mechanisms involved in wound repair and to evaluate novel therapies for skin wounds [4]. Recently, the team also highlighted the ability of equine MSCs to target and destroy pathogenic bacteria from within skin wounds via the secretion of antimicrobial peptides [5]. 

In their new STEM CELLS Translational Medicine article [6], the team now report on the ability of equine MSCs to disrupt biofilms generated by a wide variety of relevant wound pathogens. The formation of biofilms, which are adherent, highly structured cellular communities encased in a self‐produced extracellular matrix, typically occurs in cutaneous wounds and fosters the development of antibiotic‐resistant wound infections and wound chronicity [7, 8]. Now, Marx et al. demonstrate that equine MSC-secreted factors can impair biofilm formation by cutaneous wound‐related bacteria and disrupt mature biofilms via a protease‐dependent mechanism.

The authors first confirmed that MSC conditioned medium (MSC-CM), which contains the secretome, inhibited the growth of cultures of free-living (planktonic) Gram-positive and -negative bacteria known to colonize cutaneous wounds, although at a lower efficacy when compared to treatment with a penicillin/streptomycin cocktail (P/S). However, the team established that the MSC secretome negatively affected the same bacteria when part of a biofilm to a greater extent than P/S treatment; in fact, MSC-CM treatment inhibited biofilm formation and disrupted established biofilms.

Importantly, the MSC secretome also hampered the growth of methicillin‐resistant Staphylococcus aureus (MRSA), which can cause serious infections due to therapeutic resistance, in both free-living and biofilm conditions. Of note, a cocktail of high-concentration conventional antibiotics failed to significantly affect MRSA under the same biofilm conditions. 

At a mechanistic level, the authors discovered that protein degradation by the cysteine protease activity present in the MSC secretome (e.g., cathepsins B and V) played a significant role in the inhibited growth of MRSA in biofilms; furthermore, the study found that MSC-derived cysteine protease activity synergized with an antibiotic cocktail to significantly disrupt established MRSA biofilms, thereby providing proof for a new and improved therapeutic approach in the battle against antibiotic-resistant bacterial strains.

Overall, the authors demonstrate for the first time that the equine MSC secretome can inhibit the growth of antibiotic‐resistant bacterial strains within biofilms through protein degradation, and they now hope that this mechanism can be fully explored using human MSCs in the near future.  The authors also hope to address some of the limitations of their study by studying more complex biofilm models and exploring other more clinically relevant antibiotics to accelerate this highly encouraging area of research.

For more on how MSC-secreted factors can help in the battle against antibiotic‐resistant bacteria, stay tuned to the Stem Cells Portal!

 

References

  1. Bussche L and Van de Walle GR, Peripheral Blood-Derived Mesenchymal Stromal Cells Promote Angiogenesis via Paracrine Stimulation of Vascular Endothelial Growth Factor Secretion in the Equine Model. STEM CELLS Translational Medicine 2014;3:1514-1525.
  2. Harman RM, He MK, Zhang S, et al., Plasminogen Activator Inhibitor-1 and Tenascin-C Secreted by Equine Mesenchymal Stromal Cells Stimulate Dermal Fibroblast Migration in vitro and Contribute to Wound Healing in vivo. Cytotherapy 2018;20:1061-1076.
  3. Bussche L, Harman RM, Syracuse BA, et al., Microencapsulated Equine Mesenchymal Stromal Cells Promote Cutaneous Wound Healing in Vitro. Stem Cell Research & Therapy 2015;6:66.
  4. Harman RM, Theoret CL, and Van de Walle GR, The Horse as a Model for the Study of Cutaneous Wound Healing. Advances in Wound Care 2019.
  5. Harman RM, Yang S, He MK, et al., Antimicrobial Peptides Secreted by Equine Mesenchymal Stromal Cells Inhibit the Growth of Bacteria Commonly Found in Skin Wounds. Stem Cell Research & Therapy 2017;8:157.
  6. Marx C, Gardner S, Harman RM, et al., The mesenchymal stromal cell secretome impairs methicillin-resistant Staphylococcus aureus biofilms via cysteine protease activity in the equine model. STEM CELLS Translational Medicine 2020;9:746-757.
  7. Rahim K, Saleha S, Zhu X, et al., Bacterial Contribution in Chronicity of Wounds. Microbial Ecology 2017;73:710-721.
  8. Bjarnsholt T, The Role of Bacterial Biofilms in Chronic Infections. APMIS 2013;121:1-58.