Regenerative and Anti-Inflammatory Potential of Regularly Fed, Starved Cells and Extracellular Vesicles In Vivo
Federico Ferro,
Renza Spelat,
Georgina Shaw,
Cynthia M. Coleman,
Xi Zhe Chen,
David Connolly,
Elisabetta M. F. Palamá,
Chiara Gentili,
Paolo Contessotto,
Mary J. Murphy
Affiliations
Federico Ferro
Department of Medical, Surgery and Health Sciences, University of Trieste, 34125 Trieste, Italy
Renza Spelat
Neurobiology Sector, International School for Advanced Studies (SISSA), 34136 Trieste, Italy
Georgina Shaw
College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), National University of Ireland Galway (NUI Galway), H91 W2T9 Galway, Ireland
Cynthia M. Coleman
College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), National University of Ireland Galway (NUI Galway), H91 W2T9 Galway, Ireland
Xi Zhe Chen
College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), National University of Ireland Galway (NUI Galway), H91 W2T9 Galway, Ireland
David Connolly
Discipline of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland, H91 TK33 Galway, Ireland
Elisabetta M. F. Palamá
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Chiara Gentili
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Paolo Contessotto
Department of Molecular Medicine, University of Padova, 35122 Padova, Italy
Mary J. Murphy
College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), National University of Ireland Galway (NUI Galway), H91 W2T9 Galway, Ireland
Background: Mesenchymal stem/stromal cells (MSC) have been employed successfully in immunotherapy and regenerative medicine, but their therapeutic potential is reduced considerably by the ischemic environment that exists after transplantation. The assumption that preconditioning MSC to promote quiescence may result in increased survival and regenerative potential upon transplantation is gaining popularity. Methods: The purpose of this work was to evaluate the anti-inflammatory and regenerative effects of human bone marrow MSC (hBM-MSC) and their extracellular vesicles (EVs) grown and isolated in a serum-free medium, as compared to starved hBM-MSC (preconditioned) in streptozotocin-induced diabetic fractured male C57BL/6J mice. Results: Blood samples taken four hours and five days after injection revealed that cells, whether starved or not, generated similar plasma levels of inflammatory-related cytokines but lower levels than animals treated with EVs. Nonetheless, starved cells prompted the highest production of IL-17, IL-6, IL-13, eotaxin and keratinocyte-derived chemokines and induced an earlier soft callus formation and mineralization of the fracture site compared to EVs and regularly fed cells five days after administration. Conclusions: Preconditioning may be crucial for refining and defining new criteria for future MSC therapies. Additionally, the elucidation of mechanisms underpinning an MSC’s survival/adaptive processes may result in increased cell survival and enhanced therapeutic efficacy following transplantation.
