Extracellular Vesicles Produced by the Cardiac Microenvironment Carry Functional Enzymes to Produce Lipid Mediators In Situ

Abstract

The impact of the polyunsaturated fatty acids (PUFAs) at physiological concentrations on the composition of eicosanoids transported within the extracellular vesicles (EVs) of rat bone marrow mesenchymal stem cells and cardiomyoblasts was reported by our group in 2020. The aim of this article was to extend this observation to cells from the cardiac microenvironment involved in the processes of inflammation, namely mouse J774 macrophages and rat heart mesenchymal stem cells cMSCs. Moreover, to enhance our capacity to understand the paracrine exchange between these orchestrators of cardiac inflammation, we investigated some machinery involved in the eicosanoid’s synthesis transported by the EVs produced by these cells (including the two formerly described cells: bone marrow mesenchymal stem cells BM-MSC and cardiomyoblasts H9c2). We analyzed the oxylipin and the enzymatic content of the EVs collected from cell cultures supplemented (or not) with PUFAs. We prove that large eicosanoid profiles are exported in the EVs by the cardiac microenvironment cells, but also that these EVs carry some critical and functional biosynthetic enzymes, allowing them to synthesize inflammation bioactive compounds by sensing their environment. Moreover, we demonstrate that these are functional. This observation reinforces the hypothesis that EVs are key factors in paracrine signaling, even in the absence of the parent cell. We also reveal a macrophage-specific behavior, as we observed a radical change in the lipid mediator profile when small EVs derived from J774 cells were exposed to PUFAs. To summarize, we prove that the EVs, due to the carried functional enzymes, can alone produce bioactive compounds, in the absence of the parent cell, by sensing their environment. This makes them potential circulating monitoring entities.

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“…Enzymes of the many lipid mediators pathways are carried by MSC and their EVs. Cardiac MSCs and their EVs carry 5-LO and 15-LO, enzymes which play a role in transforming PUFAs in SPMs ( 123 ). Thus, these enzymes are able to modify dynamically the concentration in various SPMs inside EVs.…”

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“…In addition to their lipidic structure, exosomes are biological vehicles that directly transfer lipids (including arachidonic acid and eicosanoid) [44] and contain various lipid transporters. Exosomes also contain a variety of enzymes involved in lipid metabolism, including phospholipases D, A2 [45], and oxilipin synthases (i.e., 5-and 15-lipoxygenase, leukotriene A4 hydrolase, and leukotriene C4 synthase, PGD synthase) [46,47].…”