The metabolic syndrome modifies the mRNA expression profile of extracellular vesicles derived from porcine mesenchymal stem cells

Abstract

BackgroundMesenchymal stem cells (MSCs) perform paracrine functions by releasing extracellular vesicles (EVs) containing microRNA, mRNA, and proteins. We investigated the mRNA content of EVs in metabolic syndrome (MetS) and tested hypothesis that comorbidities interfere with the paracrine functionality of MSCs.MethodsMesenchymal stem cells were collected from swine abdominal adipose tissue after 16 weeks of a low- (Lean) or high-calorie (MetS) diet (n = 5 each). We used next-generation mRNAs sequencing to identify mRNAs enriched and depleted in Lean- or MetS-EVs compared to the parent MSCs.ResultsWe found 88 and 130 mRNAs enriched in Lean-EVs and MetS-EVs, respectively, of which only eight were common genes encoding proteins related to the nucleus, endoplasmic reticulum, and membrane fraction. Lean-EVs were enriched with mRNAs primarily involved in transcription regulation and the transforming growth factor (TGF)-β signaling pathway, but devoid of genes related to regulation of inflammation. In contrast, MetS-EVs contained mRNAs involved in translational regulation and modulation of inflammation mediated by chemokines and cytokines, but lacked mRNAs related to TGF-β signaling. mRNAs enriched in EVs have the potential to target a significant proportion of genes enriched in EVs, but only 4% microRNA target genes overlap between Lean- and MetS-EVs. Co-culture with MetS-EVs also increased renal tubular cell inflammation in-vitro.ConclusionsMetabolic syndrome may affect immunomodulatory function of porcine MSCs by modifying mRNA profiles of the EVs that they produce and post-transcriptional regulation. These observations may have important implications for cell-based therapy, and support development of strategies to improve the efficacy of MSCs and their EVs.Electronic supplementary materialThe online version of this article (10.1186/s13098-018-0359-9) contains supplementary material, which is available to authorized users.

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

“…This may in turn induce expression of genes encoding for several proinflammatory cytokines, impairing the immunomodulatory potential of MSCs in subjects with MetS. Indeed, we found that expression of the proinflammatory cytokines TNF-α, MCP-1 IL-6, and IL-1β was higher in renal tubular cells cocultured with MetS-EVs compared with cells untreated or cocultured with Lean-EVs, extending our previous observations [41]. Nevertheless, proliferation capacity of PK1 cells was unaltered following coincubation with either Lean-or MetS-EVs, arguing against major effect of these inflammatory pathways on proliferation of renal tubular cells.…”

Alterations in genetic and protein content of swine adipose tissue-derived mesenchymal stem cells in the metabolic syndrome

“…We acknowledge several limitations to this study, including a modest number of samples and inability to identify MSC post-translational/epigenetic changes. MSC at the 3rd passage possess a phenotype comparable to their parent cells (51), and we have previously validated trends observed in RNAseq using PCR and Western Blots (17, 51–55). Future studies will also need to define the functional limitations that MetS impose on MSC, and the mechanisms by which it modifies genetic and protein cellular information.…”

Extracellular Vesicles from Mesenchymal Stem Cells Exert Pleiotropic Effects on Amyloid‐β, Inflammation, and Regeneration: A Spark of Hope for Alzheimer's Disease from Tiny Structures?

“…This is fairly plausible, considering that physiologically MSCs reside in niches characterized by a low oxygen tension (hypoxia), albeit inhibitory effects of hypoxia on the proliferative and differentiation abilities of MSCs have been demonstrated in vitro . In addition, exposing MSCs to different metabolic conditions, such as diabetes, which is a pathological condition predisposing to AD, can modify characteristics of the obtained EVs . Therefore it should be carefully considered that the in vitro and in vivo states of MSCs could determine different effectiveness of EVs.…”