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

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.

Adipose Stromal/Stem Cell-Derived Extracellular Vesicles: Potential Next-Generation Anti-Obesity Agents

“…Similar data have been obtained in swine [44]. Scientific evidence has indicated that obesity can alter the miRNA content of ASC-derived EVs as well as the ability of these nanoparticles to modulate important injury pathways in the recipient cells [43,45]. Data from human subjects showed that eight miRNAs were upregulated and 75 miRNAs were downregulated in obese EVs vs. lean EVs.…”

“…The miRNAs are small single-stranded non-coding RNA molecules (containing about 22 nucleotides) present in all living organisms that function in RNA silencing and posttranscriptional regulation of gene expression. In humans, the literature shows that the size, but not the number, of ASC-derived EVs from obese individuals is smaller than those from lean individuals [43]. Similar data have been obtained in swine [44].…”

“…While upregulated miRNAs from ASC-derived EVs of obese subjects were involved in the modulation of nuclear factor kB (NF-kB) and mitogen-activated protein kinase (MAPK) signals, as well as in cytoskeleton organization and apoptosis, those downregulated in the same EVs were implicated in the cell cycle and angiogenesis, and in modulating other signals such as those transduced by the Wnt and MAPK molecular pathways. The authors suggested that treating damaged human proximal tubular epithelial cells (HK2 cells) with ASC-derived EVs obtained from obese individuals were less effective at reducing inflammatory reaction and apoptosis than the corresponding EVs isolated from ASCs of lean subjects [43]. Similarly, intrarenal delivery of EVs obtained from ASCs of obese swine was unable to preserve the microcirculation and improve function in pigs with renovascular disease [45].…”

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease

“…Differential expression analysis of these EVs allows us to distinguish between lean and obese patients, identifying upregulated miRNAs that mediate the inflammatory response and downregulated miRNAs implicated in cell proliferation and angiogenesis, in obese patients. [168] Castaño et al found that obesity changes the miRNA profile of plasma exosomes in mice, including increases in miR-122, miR-192, miR-27a-3p and miR-27b-3p [73]. Likewise, exosomal miR-20b-5p has been associated with type-2 diabetes in humans [88].…”

Adipose stem cells-released extracellular vesicles as a next-generation cargo delivery vehicles: a survey of minimal information implementation, mass production and functional modification

“…EVs is the generic term for several subtypes of particles naturally released from the native cells, such as “exosome”, “microparticle/microvesicle”, “ectosome”, “oncosome”, “apoptotic body” and many other names [ 8 ]. With a size of about 50–200 nm, exosome is a subset of endosome-origin small EVs, known as a heterogeneous mixture of microRNA-assembled, protein-decorated and lipid-bound nanoparticles [ 9 – 11 ]. The last decades has witnessed a dramatically increasing number of scientific publications on ASCs EVs, opening new frontiers for a next-generation drug delivery platform in ASCs-based regenerative [ 10 ].…”