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. 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. 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. 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.

中文翻译：

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代谢综合征会增加猪和人间充质干细胞/基质细胞的细胞外囊泡中与衰老相关的 micro-RNA。


代谢综合征 (MetS) 是心血管危险因素的组合，包括肥胖、高血压、高血糖和胰岛素抵抗。 MetS 可能会诱导间充质干细胞/基质细胞 (MSC) 衰老并影响其微小 RNA (miRNA) 含量。我们假设 MetS 还会改变 MSC 衍生的细胞外囊泡 (EV) 中与衰老相关 (SA) 的 miRNA，并干扰其功能。 EV 是从腹部脂肪组织来源的 MSC 中收集的，这些 MSC 来自饮食诱导的 MetS 或瘦肉对照组（n = 6 只）以及 MetS 患者（n = 4）或年龄匹配的瘦肉对照组（n = 5）。进行 miRNA 测序以识别这些 EV 中失调的 miRNA，并进行基因本体分析以分析失调 miRNA 所针对的 SA 基因。为了测试 EV 功能，MetS 和瘦肉猪 EV 与肾小管细胞在体外共同孵育，或在体内注射到患有肾血管疾病的猪（RVD，各 n = 6）中。 SA-b-半乳糖苷酶和三色染色分别评估细胞衰老和纤维化。患有 MetS 的人和猪都表现出肥胖、高血压和高血糖/胰岛素抵抗。在 MetS 猪中，一些上调和下调的 miRNA 靶向 MSC-EV 中的 5768 个基因，其中 68 个是 SA。在 MetS 患者中，下调和上调的 miRNA 靶向 131 个 SA 基因，其中 57 个与猪 EV miRNA 靶点重叠。在体外，MetS-MSC-EV 比 Lean-MSC-EV 更能诱导肾小管细胞衰老。在体内，Lean-MSC-EV 比 MetS-MSC-EV 更有效地减轻肾脏衰老、纤维化和功能障碍。 MetS 上调猪 MSC-EV 中的 SA-miRNA（这在人类受试者中是保守的），并减弱其抑制细胞衰老和修复受损靶器官的能力。 在设计再生治疗方法时需要考虑这些改变。