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Metabolic Syndrome Promotes a Pro-inflammatory Profile in MSC-derived Extracellular Vesicles

Review of “Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell‐Derived Extracellular Vesicles” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Recent research from the laboratory of Lilach O. Lerman (Mayo Clinic, Rochester, Minnesota, USA) revealed that metabolic syndrome, a cluster of conditions increase the risk of heart disease, stroke and type 2 diabetes, modifies insulin signaling-related mRNA expression in porcine adipose tissue‐derived mesenchymal stem cells (MSCs) [1]. Additionally, metabolic syndrome also modulated the microRNA cargo of MSC-released extracellular vesicles (EVs) and interfered with pathways related to the development of metabolic syndrome and its numerous complications [2]. 

Now, the team returns with a STEM CELLS Translational Medicine study in which they examine how metabolic syndrome-induced modulation of protein‐coding genes in porcine adipose tissue‐derived MSCs modifies the expression of proteins packed within their EVs [3]. Interestingly, Eirin et al. discovered that metabolic syndrome promoted a pro‐inflammatory profile in MSC-EVs and hypothesized that such an alteration might impair the recently postulated therapeutic ability of EVs [4, 5].

The authors employed chromatography-mass spectrometry proteomic analysis to compare the protein cargos of MSCs and EVs derived from the abdominal fat of pigs fed for 16 weeks on lean or metabolic syndrome-inducing diets. Subsequent analysis of protein expression discovered the upregulation of 146 proteins and the downregulation of 273 in a comparison of lean EVs and lean MSCs, and the upregulation of 787 proteins and the downregulation of 185 in metabolic syndrome EVs versus metabolic syndrome MSCs. 

In general, those proteins enriched in both lean and metabolic syndrome EVs participated in vesicle‐mediated transport and cell‐to‐cell communication, as expected; however, the EVs derived from pigs under different feeding regimens displayed alterations to the packaging of proteins with the potential to influence repair of damaged tissues. While lean EVs displayed high levels of proteins related to the reparative capacity of MSCs, including proteins involved in cell proliferation, differentiation, division, and activation, as well as TGF‐β signaling, metabolic syndrome EVs instead displayed an enrichment for proteins related to pro‐inflammatory pathways, such as proteins involved in acute inflammatory responses, leukocyte transendothelial migration, and cytokine production. Importantly, renal tubular cells (PK1) exhibited signs of inflammation, such as NF‐kB activation and the expression of the pro‐inflammatory cytokines TNF‐α, MCP‐1 IL‐6, and IL‐1β, following coculture with the metabolic syndrome EVs.

While the authors note that their study suffers from small sample size and the short duration of the metabolic syndrome-inducing diet when compared to the human disease, they still believe that their findings still caution against the therapeutic application of autologous MSCs in patients with metabolic syndrome. Prospective studies will include the description of the impact of each independent component of metabolic syndrome on EV protein cargo alterations with the hope of discovering a means to reverse their pro-inflammatory nature.

For more on MSCs, extracellular vesicles, and metabolic syndrome, stay tuned to the Stem Cells Portal!

References

  1. Conley SM, Zhu XY, Eirin A, et al., Metabolic syndrome alters expression of insulin signaling-related genes in swine mesenchymal stem cells. Gene 2018;644:101-106.
  2. Meng Y, Eirin A, Zhu XY, et al., The metabolic syndrome alters the miRNA signature of porcine adipose tissue-derived mesenchymal stem cells. Cytometry A 2018;93:93-103.
  3. Eirin A, Zhu X-Y, Woollard JR, et al., Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles. STEM CELLS Translational Medicine 2019;8:430-440.
  4. Eirin A, Zhu XY, Puranik AS, et al., Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney International 2017;92:114-124.
  5. Shigemoto-Kuroda T, Oh JY, Kim DK, et al., MSC-derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis. Stem Cell Reports 2017;8:1214-1225.