Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume -, Issue 10, Pages 1350-1362Publisher
ELSEVIER
DOI: 10.1016/j.bbalip.2019.06.010
Keywords
Specialized proresolving mediator; Prostaglandin E-2; Phospholipid; Cell therapy
Funding
- Clinical State Research Funding [EVO/VTR grant, Finland]
- Finnish Cultural Foundation
- Business Finland [NANOSKIN grant] [4708/31/2016]
- Wellcome Trust Infrastructure Grant [101604/Z/13/Z]
- Academy of Finland [287089]
- Magnus Ehrnrooth Foundation
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [677542]
- Barts Charity [MGU0343]
- Sir Henry Dale Fellowship - Wellcome Trust [107613/Z/15/Z]
- Sir Henry Dale Fellowship - Royal Society [107613/Z/15/Z]
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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 E-2 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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