Metabolic syndrome increases senescence-associated micro-RNAs in extracellular vesicles derived from swine and human mesenchymal stem/stromal cells.
BACKGROUND
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. We hypothesized that MetS also alters senescence-associated (SA) miRNAs in MSC-derived extracellular vesicles (EVs), and interferes with their function.


METHODS
EVs 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.


RESULTS
Both 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.


CONCLUSIONS
MetS 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. Video abstract.
['Li|Yongxin|Y|', 'Meng|Yu|Y|', 'Zhu|Xiangyang|X|', 'Saadiq|Ishran M|IM|', 'Jordan|Kyra L|KL|', 'Eirin|Alfonso|A|', 'Lerman|Lilach O|LO|0000-0002-3271-3887']
D000328:Adult D000818:Animals D002460:Cell Line D016922:Cellular Senescence D004195:Disease Models, Animal D000067128:Extracellular Vesicles D005260:Female D005786:Gene Expression Regulation D006801:Humans D007668:Kidney D059630:Mesenchymal Stem Cells D024821:Metabolic Syndrome D035683:MicroRNAs D013552:Swine D013851:Thinness D055815:Young Adult
Metabolic syndrome Senescence MSC EV RNA-sequencing