Metabolic syndrome increases senescence-associated micro-RNAs in extracellular vesicles derived from swine and human mesenchymal stem/stromal cells

Yongxin Li,Yu Meng,Xiangyang Zhu,Ishran M Saadiq,Alfonso Eirin,Kyra L Jordan,Lilach O Lerman

doi:10.1186/s12964-020-00624-8

Abstract

BackgroundThe metabolic syndrome (MetS) is a combination of cardiovascular risk-factors, including obesity, hypertension, hyperglycemia, and insulin resistance. MetS may induce senescence in mesenchymal stem/stromal cells (MSC) and impact their micro-RNA (miRNA) content. We hypothesized that MetS also alters senescence-associated (SA) miRNAs in MSC-derived extracellular vesicles (EVs), and interferes with their function.MethodsEVs were collected from abdominal adipose tissue-derived MSCs from pigs with diet-induced MetS or Lean controls (n = 6 each), and from patients with MetS (n = 4) or age-matched Lean controls (n = 5). MiRNA sequencing was performed to identify dysregulated miRNAs in these EVs, and gene ontology to analyze their SA-genes targeted by dysregulated miRNAs. To test for EV function, MetS and Lean pig-EVs were co-incubated with renal tubular cells in-vitro or injected into pigs with renovascular disease (RVD, n = 6 each) in-vivo. SA-b-Galactosidase and trichrome staining evaluated cellular senescence and fibrosis, respectively.ResultsBoth humans and pigs with MetS showed obesity, hypertension, and hyperglycemia/insulin resistance. In MetS pigs, several upregulated and downregulated miRNAs targeted 5768 genes in MSC-EVs, 68 of which were SA. In MetS patients, downregulated and upregulated miRNAs targeted 131 SA-genes, 57 of which overlapped with pig-EVs miRNA targets. In-vitro, MetS-MSC-EVs induced greater senescence in renal tubular cells than Lean-MSC-EVs. In-vivo, Lean-MSC-EVs attenuated renal senescence, fibrosis, and dysfunction more effectively than MetS-MSC-EVs.ConclusionsMetS upregulates SA-miRNAs in swine MSC-EVs, which is conserved in human subjects, and attenuates their ability to blunt cellular senescence and repair injured target organs. These alterations need to be considered when designing therapeutic regenerative approaches.6zqxia-CrPNCC_V2gsDzjqVideo abstractGraphical abstract

Highlights

The metabolic syndrome (MetS) is a combination of cardiovascular risk-factors, including obesity, hypertension, hyperglycemia, and insulin resistance
We have shown that MetS modulates mesenchymal stem/stromal cells (MSC) expression of senescenceassociated (SA)-miRNAs [12], but whether this alteration extends to their paracrine extracellular vesicles (EVs), or interferes with their ability to suppress SA mechanisms in target cells, remains known
The current study shows that MetS increases the content of senescence-associated miRNAs in MSCs-derived EVs in both a pig model and human subjects

Summary

Introduction

The metabolic syndrome (MetS) is a combination of cardiovascular risk-factors, including obesity, hypertension, hyperglycemia, and insulin resistance. MetS may induce senescence in mesenchymal stem/stromal cells (MSC) and impact their micro-RNA (miRNA) content. Cellular senescence is an important cell fate, which entails apoptosis-resistance, stable replicative arrest, acquisition of a pro-inflammatory, tissue-destructive senescence-associated (SA) secretory phenotype (SASP), and shifted metabolism [4]. During this process, fatty acid oxidation is decreased, but protein synthesis and generation of reactive oxygen species increase [5]. We have previously shown that MetS impairs the functionality of MSCs, increases their cellular senescence [9], and alters their genetic and protein content [10,11,12]

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