Metabolic syndrome increases senescence-associated micro-RNAs in extracellular vesicles derived from swine and human mes
- PDF / 1,477,338 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 53 Downloads / 181 Views
(2020) 18:124
RESEARCH
Open Access
Metabolic syndrome increases senescenceassociated micro-RNAs in extracellular vesicles derived from swine and human mesenchymal stem/stromal cells Yongxin Li1,2, Yu Meng3, Xiangyang Zhu1, Ishran M. Saadiq1, Kyra L. Jordan1, Alfonso Eirin1 and Lilach O. Lerman1*
Abstract 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 senescenceassociated (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. Keywords: Metabolic syndrome, MSC, EV, RNA-sequencing, Senescence
* Correspondence: [email protected] 1 Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not include
Data Loading...
