University of Oulu

Minna Holopainen, Romain A. Colas, Sami Valkonen, Feven Tigistu-Sahle, Kati Hyvärinen, Francesca Mazzacuva, Petri Lehenkari, Reijo Käkelä, Jesmond Dalli, Erja Kerkelä, Saara Laitinen, Polyunsaturated fatty acids modify the extracellular vesicle membranes and increase the production of proresolving lipid mediators of human mesenchymal stromal cells, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Volume 1864, Issue 10, 2019, Pages 1350-1362, ISSN 1388-1981, https://doi.org/10.1016/j.bbalip.2019.06.010

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

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Author: Holopainen, Minna1,2; Colas, Romain A.3; Valkonen, Sami1,4;
Organizations: 1Finnish Red Cross Blood Service, Helsinki, Finland
2Helsinki 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
3Lipid Mediator Unit, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
4EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
5Department of Anatomy and Surgery, Institute of Translational Medicine, University of Oulu and Clinical Research Centre, Oulu, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2019111838457
Language: English
Published: Elsevier, 2019
Publish Date: 2020-06-15
Description:

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.

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Series: Biochimica et biophysica acta. Molecular and cell biology of lipids
ISSN: 1388-1981
ISSN-E: 1879-2618
ISSN-L: 1388-1981
Volume: 10
Pages: 1350 - 1362
DOI: 10.1016/j.bbalip.2019.06.010
OADOI: https://oadoi.org/10.1016/j.bbalip.2019.06.010
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This work was supported by Clinical State Research Funding [EVO/VTR grant, Finland] (M.H.), Finnish Cultural Foundation (M.H.), and Business Finland [NANOSKIN grant no: 4708/31/2016] (S.V, S.L). This work is also funded by a Wellcome Trust Infrastructure Grant [Ref 101604/Z/13/Z], Academy of Finland [grant no: 287089], and Magnus Ehrnrooth Foundation (S.V.). J.D. received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [grant no: 677542] and the Barts Charity [grant no: MGU0343]. J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society [grant 107613/Z/15/Z].
Copyright information: © 2019 Elsevier B.V. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
  https://creativecommons.org/licenses/by-nc-nd/4.0/