Metabolic Syndrome Induces Release of Smaller Extracellular Vesicles from Porcine Mesenchymal Stem Cells

Conley, Sabena M.; Shook, John E.; Zhu, Xiang Yang; Eirin, Alfonso; Jordan, Kyra L.; Woollard, John R.; Isik, Busra; Hickson, La Tonya J.; Puranik, Amrutesh S.; Lerman, Lilach O.

doi:10.1177/0963689719860840

Cited by 23 publications

(18 citation statements)

References 31 publications

(49 reference statements)

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“…The current study shows that obesity alters the size and miRNA cargo of human ASC-derived EVs. The number of EVs released from lean-and obese-ASCs was similar, but obese-EVs were smaller compared to lean-EVs, in line with our previous observations in swine obese-EVs (Conley et al, 2019). miRNAs upregulated in obese-EVs target preferentially clusters of genes participating in regulation of NF-kB and MAPK signaling, cytoskeleton organization, and apoptosis, whereas miRNAs downregulated in obese-EVs target groups of genes implicated in cell cycle, angiogenesis, and MAPK and Wnt signaling.…”

Section: Discussionsupporting

confidence: 91%

The Micro-RNA Cargo of Extracellular Vesicles Released by Human Adipose Tissue-Derived Mesenchymal Stem Cells Is Modified by Obesity

Eirin

Meng

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Obesity is a chronic disease that interferes with normal repair processes, including adipose mesenchymal stem/stromal cells (ASCs) function. ASCs produce extracellular vesicles (EVs) that activate a repair program in recipient cells partly via their micro-RNA (miRNA) cargo. We hypothesized that obesity alters the miRNA expression profile of human ASC-derived EVs, limiting their capacity to repair injured cells. Human ASCs were harvested from obese and age- and gender-matched non-obese (lean) subjects during bariatric or cosmetic surgeries, respectively (n = 5 each), and their EVs isolated. Following high-throughput sequencing analysis, differentially expressed miRNAs were identified and their gene targets classified based on cellular component, molecular function, and biological process. The capacity of human lean- and obese-EVs to modulate inflammation, apoptosis, as well as mitogen-activated protein kinase (MAPK) and Wnt signaling in injured human proximal tubular epithelial (HK2) cells was evaluated in vitro. The number of EVs released from lean- and obese-ASCs was similar, but obese-EVs were smaller compared to lean-EVs. Differential expression analysis revealed 8 miRNAs upregulated (fold change > 1.4, p < 0.05) and 75 downregulated (fold change < 0.7, p < 0.05) in obese-EVs vs. lean-EVs. miRNAs upregulated in obese-EVs participate in regulation of NFk-B and MAPK signaling, cytoskeleton organization, and apoptosis, whereas those downregulated in obese-EVs are implicated in cell cycle, angiogenesis, and Wnt and MAPK signaling. Treatment of injured HK2 cells with obese-EVs failed to decrease inflammation, and they decreased apoptosis and MAPK signaling significantly less effectively than their lean counterparts. Obesity alters the size and miRNA cargo of human ASC-derived EVs, as well as their ability to modulate important injury pathways in recipient cells. These observations may guide development of novel strategies to improve healing and repair in obese individuals.

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Section: Discussionsupporting

confidence: 91%

The Micro-RNA Cargo of Extracellular Vesicles Released by Human Adipose Tissue-Derived Mesenchymal Stem Cells Is Modified by Obesity

Eirin

Meng

Zhu

et al. 2021

Front. Cell Dev. Biol.

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“…Furthermore, we have also shown that MetS can modify the cargo and size of porcine adipose tissue-derived MSC, including mRNAs, miRNAs, and proteins, which might in turn control some important cellular functions (15,16). In addition, the transcriptome and proteome of particularly genes in MSCs involved in mitochondria, inflammation, and transcription regulation were found to be altered in MetS (17).…”

Section: Introductionmentioning

confidence: 97%

Metabolic Syndrome Is Associated With Altered mRNA and miRNA Content in Human Circulating Extracellular Vesicles

Meng

Zhu

et al. 2021

Front. Endocrinol.

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As mediators of intercellular communication, circulating extracellular vehicles (EVs) can modulate tissue and cellular pathways by altering transcription profiles in recipient cells, and their content may reflect the status of their parent cells. However, whether their cargo is altered in the metabolic syndrome (Mets) remains unclear. We hypothesized that MetS altered mRNAs and miRNAs packed within circulating-EVs. EVs were collected from plasma of patients with MetS or age-matched Lean controls (n=4 each). RNA sequencing was performed to identify dysregulated mRNAs and miRNAs, and analyze genes targeted by miRNAs, top pathways, and diseases associated with MetS-EVs. MetS patients showed elevated body weight, blood pressure, glucose, insulin, and liver injury markers levels. 1,446 mRNAs were downregulated and 32 upregulated in MetS- compared to Lean-EVs, whereas 40 miRNAs were selectively enriched and 10 downregulated in MetS-EVs. MetS upregulated in EVs genes involved in apoptosis, mitochondrial regulation, transport, and lipoproteins, but downregulated vessel and heart development, protein complex biogenesis, and angiogenesis. MetS also upregulated miRNAs targeting genes implicated in cellular processes, including oxidation–reduction, and downregulated miRNAs capable of modulating catalytic activity, as well as heart, blood vessel, and skeletal development, transcriptional regulation, apoptosis, and cell cycle. Our study, thus, indicates that human subjects with MetS show modified cargo of circulating EVs, which in turn may modulate several critical cellular functions and fate. These EVs may reflect the anomalous status of their parent cells, and potentially serve as important regulators, biomarkers, and targets in the progression and treatment of MetS.

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“…Consequently, MetS-induced changes in the content and function of adipose tissue-derived MSCs may also impact on their EV progeny. Recently, we reported that swine MetS altered the size distribution of MSCderived EVs compared with those obtained from lean pigs toward smaller vesicles packed with genes commonly associated with exosomes (8), although the overall EV number released by MetS MSCs remained unchanged. MetS also modulates the mRNA cargo packed within porcine adipose tissue MSC-derived EVs, which contain genes involved in translational regulation and modulation of inflammation (39).…”

Section: Cardiovascular Risk Factors and Evsmentioning

confidence: 90%

Stem cell-derived extracellular vesicles for renal repair: do cardiovascular comorbidities matter?

Eirin

Lerman

2019

American Journal of Physiology-Renal Physiology

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Extracellular vesicle (EV)-based regenerative therapy has shown promising results in preclinical models of renal disease and might be useful for patients with several forms of chronic kidney disease. However, individuals with chronic kidney disease often present with comorbidities, including obesity, hypertension, diabetes, or even metabolic syndrome, which may alter the endogenous characteristics and impair the reparative capacity of stem cells and their daughter EVs. This brief review summarizes evidence of alterations in the morphology, cargo, and function of mesenchymal stem cells and mesenchymal stem cell-derived EVs in the face of cardiovascular disease. We further discuss the important ramifications for their use in patients with kidney disease.

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Metabolic Syndrome Induces Release of Smaller Extracellular Vesicles from Porcine Mesenchymal Stem Cells

Cited by 23 publications

References 31 publications

The Micro-RNA Cargo of Extracellular Vesicles Released by Human Adipose Tissue-Derived Mesenchymal Stem Cells Is Modified by Obesity

The Micro-RNA Cargo of Extracellular Vesicles Released by Human Adipose Tissue-Derived Mesenchymal Stem Cells Is Modified by Obesity

Metabolic Syndrome Is Associated With Altered mRNA and miRNA Content in Human Circulating Extracellular Vesicles

Stem cell-derived extracellular vesicles for renal repair: do cardiovascular comorbidities matter?

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