Eirin Alfonso, Meng Yu, Zhu Xiang-Yang, Li Yongxin, Saadiq Ishran M, Jordan Kyra L, Tang Hui, Lerman Amir, van Wijnen Andre J, Lerman Lilach O
Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States.
Department of Nephrology, The First Hospital Affiliated to Jinan University, Guangzhou, China.
Front Cell Dev Biol. 2021 May 20;9:660851. doi: 10.3389/fcell.2021.660851. eCollection 2021.
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 ( = 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 . 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, < 0.05) and 75 downregulated (fold change < 0.7, < 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.
肥胖是一种干扰正常修复过程的慢性疾病，包括脂肪间充质干/基质细胞（ASC）的功能。ASC产生细胞外囊泡（EV），这些囊泡部分通过其微小RNA（miRNA）货物激活受体细胞中的修复程序。我们假设肥胖会改变人ASC衍生的EV的miRNA表达谱，限制其修复受损细胞的能力。在减肥手术或整形手术期间，分别从肥胖以及年龄和性别匹配的非肥胖（瘦）受试者中收集人ASC（每组n = 5），并分离其EV。经过高通量测序分析，鉴定出差异表达的miRNA，并根据细胞成分、分子功能和生物学过程对其基因靶点进行分类。评估了人瘦EV和肥胖EV调节受损人近端肾小管上皮（HK2）细胞炎症、凋亡以及丝裂原活化蛋白激酶（MAPK）和Wnt信号传导的能力。瘦ASC和肥胖ASC释放的EV数量相似，但肥胖EV比瘦EV小。差异表达分析显示，与瘦EV相比，肥胖EV中有8种miRNA上调（倍数变化> 1.4，P < 0.05），75种下调（倍数变化< 0.7，P < 0.05）。肥胖EV中上调的miRNA参与NFk - B和MAPK信号传导、细胞骨架组织和凋亡的调节，而肥胖EV中下调的miRNA与细胞周期、血管生成以及Wnt和MAPK信号传导有关。用肥胖EV处理受损的HK2细胞未能减轻炎症，并且它们降低凋亡和MAPK信号传导的效果明显低于瘦EV。肥胖会改变人ASC衍生的EV的大小和miRNA含量，以及它们调节受体细胞中重要损伤途径的能力。这些观察结果可能指导开发新策略以改善肥胖个体的愈合和修复。
