Resolution-phase macrophage population orchestrates active dampening of the inflammation by secreting anti-inflammatory and proresolving products including interleukin (IL)-10 and lipid mediators (LMs). We investigated the effects of both human bone marrow-derived mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) on mature human regulatory macrophages (Mregs). The cytokines and LMs were determined from cell culture media of Mregs cultivated with MSCs and MSC-EVs. In addition, the alterations in the expression of cell surface markers and the phagocytic ability of Mregs were investigated. Our novel findings indicate that both MSC coculture and MSC-EVs downregulated the production of IL-23 and IL-22 enhancing the anti-inflammatory phenotype of Mregs and amplifying proresolving properties. The levels of prostaglandin E2 (PGE2) were substantially upregulated in MSC coculture media, which may endorse proresolving LM class switching. In addition, our results manifest, for the first time, that MSC-EVs mediate the Mreg phenotype change via PGE2. These data suggest that both human MSC and MSC-EVs may potentiate tolerance-promoting proresolving phenotype of human Mregs.

The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor ( MDGI / FABP 3 ) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization ( LMP ). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP ‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence.

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Please cite this article as: M. Holopainen, R.A. Colas, S. Valkonen, et al., Polyunsaturated fatty acids modify the extracellular vesicle membranes and increase the production of proresolving lipid mediators of human mesenchymal stromal cells, BBA-Molecular and Cell Biology of Lipids,