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

doi:10.3390/cells11172696

Regenerative and Anti-Inflammatory Potential of Regularly Fed, Starved Cells and Extracellular Vesicles In Vivo

Cells. 2022 Aug 30;11(17):2696. doi: 10.3390/cells11172696.

Authors

Affiliations

¹ Department of Medical, Surgery and Health Sciences, University of Trieste, 34125 Trieste, Italy.
² 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.
³ Neurobiology Sector, International School for Advanced Studies (SISSA), 34136 Trieste, Italy.
⁴ Discipline of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland, H91 TK33 Galway, Ireland.
⁵ Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy.
⁶ Department of Molecular Medicine, University of Padova, 35122 Padova, Italy.

Abstract

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.

Keywords: bone micro-computed; diabetes; extracellular vesicles; inflammation; injury/fracture healing; mesenchymal stem/stromal cells; starvation tomography (μCT).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines
Extracellular Vesicles* / transplantation
Humans
Inflammation / therapy
Male
Mesenchymal Stem Cell Transplantation* / methods
Mesenchymal Stem Cells* / metabolism
Mice
Mice, Inbred C57BL

Substances

Cytokines

Grants and funding

This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement number 667932 (Autostem). The material presented and views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out. This work was also supported by Science Foundation Ireland (SFI 09/SRC.B1794) and the European Union’s Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement number 223298. The authors acknowledge the facilities and scientific and technical assistance of the μCT facility, Discipline of Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland Galway, Ireland, funded by Science Foundation Ireland under grant number SFI 12/RI/2338.