干细胞衍生的细胞外囊泡对非酒精性脂肪性肝炎的多方面作用

Multifaceted action of stem cell-derived extracellular vesicles for nonalcoholic steatohepatitis.

作者信息

Kim Jimin, Lee Seul Ki, Jeong Seon-Yeong, You Haedeun, Han Sang-Deok, Park Somi, Kim Soo, Kim Tae Min

机构信息

Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea.

Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea; Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea.

出版信息

J Control Release. 2023 Oct 27. doi: 10.1016/j.jconrel.2023.10.045.

DOI:10.1016/j.jconrel.2023.10.045

PMID:39491172

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with metabolic syndrome. Extracellular vesicles (EVs) are essential signaling mediators containing functional biomolecules. EVs are secreted from various cell types, and recent studies have shown that mesenchymal stem cell-derived EVs have therapeutic potential against immune and metabolic diseases. In this study, we investigated whether EVs from induced mesenchymal stem cells (iMSC-EVs) regulate AMPK signaling and lipid metabolism using cell-based studies and two different mouse models of NASH (methionine/choline-deficient diet-induced and ob/ob mice). Protein analysis revealed that iMSC-EVs carry cargo proteins with the potential to regulate lipid metabolism. iMSC-EVs inhibited free fatty acid release from adipose tissues by downregulating the activity of lipolytic genes in NASH. In addition, iMSC-EVs improved hepatic steatosis by modulating AMPK signaling, which plays essential role in metabolic homeostasis in the liver. Moreover, iMSC-EVs reduced CD36 expression, contributing to the blockade of free fatty acid transport to the liver of NASH mice. Finally, iMSC-EVs reduced inflammation, endoplasmic reticulum stress, and apoptosis while promoting hepatic regeneration of the NASH liver. In conclusion, iMSC-EVs can potentially serve as cell-free therapeutics for NASH owing to their multifaceted modality.

摘要

非酒精性脂肪性肝炎（NASH）是一种与代谢综合征相关的慢性肝病。细胞外囊泡（EVs）是含有功能性生物分子的重要信号介质。EVs由多种细胞类型分泌，最近的研究表明，间充质干细胞衍生的EVs对免疫和代谢疾病具有治疗潜力。在本研究中，我们使用细胞实验和两种不同的NASH小鼠模型（蛋氨酸/胆碱缺乏饮食诱导的和ob/ob小鼠），研究了诱导间充质干细胞来源的EVs（iMSC-EVs）是否调节AMPK信号通路和脂质代谢。蛋白质分析显示，iMSC-EVs携带具有调节脂质代谢潜力的货物蛋白。iMSC-EVs通过下调NASH中脂解基因的活性来抑制脂肪组织中游离脂肪酸的释放。此外，iMSC-EVs通过调节AMPK信号通路改善肝脂肪变性，AMPK信号通路在肝脏代谢稳态中起重要作用。此外，iMSC-EVs降低了CD36的表达，有助于阻断游离脂肪酸向NASH小鼠肝脏的转运。最后，iMSC-EVs减少了炎症、内质网应激和细胞凋亡，同时促进了NASH肝脏的肝再生。总之，iMSC-EVs因其多方面的作用方式，有可能作为NASH的无细胞治疗方法。