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Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1350-1362. doi: 10.1016/j.bbalip.2019.06.010. Epub 2019 Jun 15.

Polyunsaturated fatty acids modify the extracellular vesicle membranes and increase the production of proresolving lipid mediators of human mesenchymal stromal cells.

Author information

1
Finnish Red Cross Blood Service, Helsinki, Finland; Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE) & Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. Electronic address: minna.holopainen@bloodservice.fi.
2
Lipid Mediator Unit, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
3
Finnish Red Cross Blood Service, Helsinki, Finland; EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
4
Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE) & Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
5
Finnish Red Cross Blood Service, Helsinki, Finland.
6
EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
7
Department of Anatomy and Surgery, Institute of Translational Medicine, University of Oulu and Clinical Research Centre, Oulu, Finland.

Abstract

Human mesenchymal stromal/stem cells (hMSCs) are used in experimental cell therapy to treat various immunological disorders, and the extracellular vesicles (hMSC-EVs) they produce have emerged as an option for cell-free therapeutics. The immunomodulatory function of hMSCs resembles the resolution of inflammation, in which proresolving lipid mediators (LMs) play key roles. Multiple mechanisms underlying the hMSC immunosuppressive effect has been elucidated; however, the impact of LMs and EVs in the resolution is poorly understood. In this study, we supplemented hMSCs with polyunsaturated fatty acids (PUFAs); arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, which serve as precursors for multiple LMs. We then determined the consequent compositional modifications in the fatty acid, phospholipid, and LM profiles. Mass spectrometric analyses revealed that the supplemented PUFAs were incorporated into the main membrane phospholipid classes with different dynamics, with phosphatidylcholine serving as the first acceptor. Most importantly, the PUFA modifications were transferred into hMSC-EVs, which are known to mediate hMSC immunomodulation. Furthermore, the membrane-incorporated PUFAs influenced the LM profile by increasing the production of downstream prostaglandin E2 and proresolving LMs, including Resolvin E2 and Resolvin D6. The production of LMs was further enhanced by a highly proinflammatory stimulus, which resulted in an increase in a number of mediators, most notably prostaglandins, while other stimulatory conditions had less a pronounced impact after a 48-h incubation. The current findings suggest that PUFA manipulations of hMSCs exert significant immunomodulatory effects via EVs and proresolving LMs, the composition of which can be modified to potentiate the therapeutic impact of hMSCs.

KEYWORDS:

Cell therapy; Phospholipid; Prostaglandin E(2); Specialized proresolving mediator

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