Abstract
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.
Highlights
Adipose mesenchymal stem/stromal cells (ASCs), multipotent cells with capacity for self-renewal and differentiation, emerged as a promising clinical cell-based therapy because of their potential for autologous transplantation
To explore the functional implications of obesity-induced changes in the extracellular vesicles (EVs) cargo, we compared the capacity of human lean- and obese-EVs in human proximal tubular epithelial cells (HK2 cells) to modulate inflammation, apoptosis, as well as mitogen-activated protein kinase (MAPK) and Wnt signaling, important processes identified in miRNA sequencing
The current study shows that obesity alters the size and miRNA cargo of human adipose mesenchymal stem/stromal cells (ASCs)-derived EVs
Summary
Adipose mesenchymal stem/stromal cells (ASCs), multipotent cells with capacity for self-renewal and differentiation, emerged as a promising clinical cell-based therapy because of their potential for autologous transplantation. These cells possess important pro-angiogenic and immunomodulatory properties, can be obtained in large amounts from several tissues, including adipose tissue, and their delivery has shown potential efficacy for the treatment of several diseases (Dominici et al, 2006). We have previously shown that EVs isolated from porcine adipose tissue-derived ASCs contain multiple miRNAs capable of modulating several cellular pathways, including angiogenesis, cellular transport, apoptosis, and proteolysis (Eirin et al, 2014)
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