外泌体在肝纤维化中的研究进展

<正>肝纤维化是各种慢性肝病的共同病理过程,是各种慢性肝病发展为肝硬化的必经之路。肝纤维化是可逆的,而晚期肝硬化难以逆转,因此探讨肝纤维的发病机制、阻断肝纤维化的进程、寻找治疗肝纤维化的靶点具有重要意义。外泌体作为细胞之间传递的小信息球,可参与细胞通讯、细胞迁移、血管新生和肿瘤细胞生长等过程。外泌体中miRNA或蛋白质等遗传分子与肝脏病理息息相关,在肝纤维化诊断中可作为潜在的分子标志物。对外泌体的研究,将有利于探索肝纤维化的发生、发展机制,     

外泌体非编码RNA在肝纤维化中的作用及机制

肝纤维化是多种慢性肝脏疾病发展为肝硬化的初始阶段,且是一个可逆的过程。外泌体作为能够携带包括蛋白、脂质、核酸等活性物质的一种细胞外囊泡亚群,参与细胞间的信号通讯,近年来备受关注。研究表明,外泌体中非编码RNA在肝纤维化的发生发展过程中起着重要作用。在此,探讨了外泌体长链非编码RNA(包括MALAT1、H19、GAS5、MEG3、PVT1和P21)、外泌体短链非编码RNA(包括微小RNA、小核仁RNA、PIWI-interacting RNA和小干扰RNA)、外泌体环状RNA在肝纤维化发生发展过程中的作用机制。总结了不同来源(如肝细胞、胆管细胞等)的外泌体携带非编码RNA主要通过影响肝星状细胞活化、增殖、迁移、转化等过程发挥作用。未来通过对外泌体非编码RNA的深入研究,有望为肝纤维化治疗药物寻找到潜在新靶点。     

外泌体与肝脏疾病的关系

外泌体是细胞经过"內吞-融合-外排"等过程形成的直径在30~100 nm的胞外囊泡。多种细胞均可以释放外泌体,这些外泌体可携带脂质、蛋白质和核酸等重要的生物分子,参与细胞间的信号转导及物质交换,调节体内多个系统的生理病理过程,其在多种肝脏疾病中发挥至关重要的作用,如肝癌、病毒性肝炎、肝纤维化、酒精性及非酒精性脂肪肝等。对外泌体在肝脏疾病中的研究进展作一综述。     

外泌体在肝病发病机制、诊断和治疗中的作用

外泌体（exosomes）是一种直径约30-100 nm、由生物膜包裹的囊泡,是细胞内的多泡体（multivesicular bodies）与胞浆膜融合的产物,可由众多不同类型的细胞通过胞吐作用（exocytosis）释放至细胞外隙或生物学体液中,其首要生物学功能是进行细胞间联络。外泌体含有细胞特异性蛋白分子、mRNAs及miRNAs等重要分子,通过将这些分子送达靶细胞而发挥细胞间联络作用,从而带来对机体有益（生理性）或有害的（病理性）潜在结果。肝脏细胞,尤其是肝细胞和胆管上皮细胞,既可释放外泌体,又是肝脏内源性外泌体和其他器官细胞来源的外泌体作用的靶细胞。尽管目前对肝脏外泌体的研究有限,但初步研究显示外泌体在肝脏的生理和病理生理过程中发挥着重要作用。外泌体参与肝细胞癌（HCC）、病毒性肝炎及肝脏炎症等的发病机制,是肝病诊断和预后判断的潜在新型分子生物标志物,也是肝病新的潜在治疗手段。本文特对肝脏外泌体的发现、功能及其对肝病潜在的诊治价值等做一简要总结。     

血吸虫病肝纤维化发病机制研究

血吸虫病引起的重要病理特征是肝纤维化,主要由于血吸虫虫卵释放可溶性虫卵抗原形成虫卵肉芽肿,刺激机体产生炎症反应,进而引起细胞外基质过量沉积而致,与肝星状细胞、T细胞及其他细胞因子密切相关。对于血吸虫病肝纤维化的细胞和调解分子机制的深入认识,将有助于发现更多的药物作用靶点,用于新药研发,指导临床治疗,给血吸虫病患者肝纤维化治疗带来新希望。     

外泌体microRNA的生物学特征及在肝纤维化发生发展中的作用

外泌体作为人体内多种细胞分泌的微型多囊泡体,存在于机体的多种体液当中,由脂质双层膜结构来保护其内含物的结构与功能稳定,携有大量microRNA(miRNA)、mRNA等活性物质。研究表明外泌体及内含物miRNA与肝纤维化的发生进展密切相关,其通过对肝星状细胞(HSC)的作用,改变HSC活化、增殖、凋亡、漂移等来调节肝纤维化的发生发展过程。通过对外泌体miRNA的生物学特点以及与肝纤维化关系的阐述,分析了其在肝纤维化发生发展、诊治及预后评估中的重要作用,指出外泌体miRNA可能成为肝纤维化诊治与预后评估的潜在新靶点。     

外泌体微RNA在缺血性卒中神经损伤及保护中的作用

外泌体是细胞经过一系列调控形成并可分泌到细胞外的膜性囊泡,其可以携带核酸、脂质和蛋白质进行细胞间的物质传递和信息交流。研究显示,外泌体微RNA(miRNAs)可参与脑正常的生理过程,也参与损伤修复等病理过程。缺血性卒中是世界范围内的严重致残、致死性疾病,卒中神经损伤或神经保护进程中涉及到众多分子变化,而外泌体中的miRNAs可能参与这些变化,成为缺血性卒中神经损伤或保护的生物标志物和潜在的治疗靶点。本研究通过对外泌体miRNAs在缺血性卒中神经损伤及保护中作用的综述,为缺血性卒中的诊断和潜在治疗提供新的方向。     

外泌体在支气管哮喘发生发展中的作用

支气管哮喘是一种反复发作的气道慢性炎症性疾病,病因及发病机制尚未完全明确,目前认为与过敏及免疫介导的炎症有关。外泌体是由细胞释放的生物性小囊泡,包含多种细胞成分,介导细胞间通讯,参与炎症反应、免疫调节等许多生物过程的发生。外泌体作为疾病的生物标志物,也可作为治疗靶点和治疗载体。本文就外泌体在支气管哮喘发生、发展过程中的...     

外泌体在HIV-1感染中的作用研究进展

外泌体是可携带宿主和病原体衍生的基因、蛋白质、脂质等物质的内生性纳米微囊,可介导细胞与细胞间的物质和信号传递,调节人体生理和病理生理过程。随着外泌体在病毒感染领域研究的开展,人们发现外泌体在HIV-1感染的发病机制中有着重要作用。本文将对外泌体参与HIV-1感染机制、感染HIV-1后细胞释放的外泌体包含成分及作用、外泌体在HIV-1诊疗中的前景等方面进行综述。     

外泌体在肝脏纤维化中的研究进展

正外泌体是由多种细胞通过胞吐作用分泌到体液中的膜包被小泡,介导细胞间信息交流以及调节细胞微环境,参与细胞生长、增殖、分化、凋亡,肿瘤生长、侵袭等多种生理病理活动。肝脏纤维化是细胞坏死以及炎症刺激等引起肝脏细胞外基质(extracellular matrices,ECMs)过量产生并沉积的病理过程。肝星状细胞(hepatic stellate cells,HSCs)受多种信号通路调     

Emerging role of exosomes in liver physiology and pathology

Exosomes can mediate intercellular communication by conveying various bioactive molecules. Plentiful evidence suggests that exosomes are involved in many liver diseases including hepatitis C virus infection, hepatitis B virus infection, hepatocellular carcinoma, liver fibrosis, cirrhosis, non‐alcoholic fatty liver disease, and alcoholic liver disease. Moreover, exosomes are present in nearly all human body fluids. Therefore, exosomal miRNA or proteins have the potential to be novel biomarkers of liver diseases. In the treatment of liver diseases, exosomes could participate in adaptive immune response and mesenchymal stem cell‐based therapy. Exosomes can also be used as vehicles for genetic materials and drug delivery.     

The role of exosomes on colorectal cancer: A review

Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo‐resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto‐oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy.     

Exosomal microRNAs as a potential therapeutic strategy in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth most com-mon cancer and the second cause of cancer-related death worldwide. The incidence of HCC is constantly increasing in correlation with the rise in diabetes and obesity, arguing for an urgent need for new developments in the treatment of this lethal cancer. Exosomes are small double-membrane vesicles loaded with distinct cargos, particularly small non-coding RNAs called microRNAs, representative of each donor cell and secreted to affect the features of neighboring cells or recipient cells located further away, like in the case of metastasis. A better understanding of the role of exosomes with a microRNA signature in cancer pathogenesis gave rise to the concept of their use as a noninvasive diagnostic biomarker and in the treatment of cancer, including HCC. In this communication, we review recent works that demonstrate that hepatic stellate cells establish an epigenetic communication with liver cancer cells, which affects their pro-malignant features. If naturally secreted patient-derived exosomes show major limitations concerning their clinical use, bio-engineered exosome mimetics that incorporate controlled components and exhibit no protumoral properties could be promising carriers for the treatment of liver cancers, which is the organ preferentially targeted by systemic injection of exosomes.     

exosomes在肺癌细胞对顺铂敏感性降低过程中的作用研究

目的研究肺癌细胞分泌的exosomes在同源细胞对顺铂的敏感性调节过程中的可能作用。方法采用超速离心和Exoquick-TC结合的方法从肺癌细胞系A549和H1975的上清液中分离出exosomes,透射电子显微镜观察其形态,western blot检测其CD63蛋白表达;共聚焦显微镜观察细胞胞吞exosomes过程;分别提取顺铂处理肺癌细胞来源exosomes和未处理肺癌细胞来源exosomes,并使用2种exosomes分别处理肺癌细胞,采用CCK-8法检测上述获得的exosomes对肺癌细胞顺铂敏感性的影响。结果透射电子显微镜下观察肺腺癌细胞来源的exosomes具有特征性的盘状结构,直径30-100 nm,western blot结果显示exosomes富含CD63蛋白;显微镜下可观察到exosomes可进入细胞;同时经顺铂处理过肺癌细胞分泌的exosomes可降低同源细胞对顺铂的敏感性。结论减少exosomes的分泌和传递可能会增加顺铂化疗的疗效,这为肺癌的治疗提供了一种新的思路。     

Circulating exosomal miRNAs as potential biomarkers for Barrett's esophagus and esophageal adenocarcinoma

Exosomes,a class of extracellular vesicles,are small membrane-bound vesicles derived from almost all cell types that can play important roles in intercellular communication.Exosomes contain proteins,lipids,and nucleic acids that are obtained from the parental cells and participate in various pathophysiological processes,including cell growth,migration,inflammation,immune regulation,and tumor pathogenesis.Moreover,exosomes might be applied in clinical settings,such as diagnosis,treatment,and outcome prediction of diseases,including various cancers.The incidence rates of Barrett's esophagus(BE) and esophageal adenocarcinoma(EAC) have increased in recent decades,and studies have proposed specific factors that may contribute to the development and progression of these diseases.However,how exosomes play a role in this pathological process needs to be clarified.Studies have identified candidate microRNAs(miRNAs) that might be related to BE/EAC.Further studies are needed to ascertain whether circulating exosomal miRNAs are altered before or after disease onset,which could also help understand the pathophysiology of and find potential targets for prevention,diagnosis,and therapy in BE/EAC.This review summarizes recent findings on the features of circulating exosomal miRNAs in BE/EAC,which could be valuable for the early diagnosis,therapeutic approaches,and outcome prediction of BE/EAC.     

Liver fibrosis and hepatic stellate cells: Etiology,pathological hallmarks and therapeutic targets

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.     

Prions and exosomes: from PrPc trafficking to PrPsc propagation

Exosomes are membrane vesicles released into the extracellular environment upon exocytic fusion of multivesicular endosomes with the cell surface. Exosome secretion can be used by cells to eject molecules targeted to intraluminal vesicles of multivesicular bodies, but particular cell types may exploit exosomes as intercellular communication devices for transfer of proteins and lipids among cells. The glycosylphosphatyidylinositol-linked prion protein (PrP) in both its normal (PrPc) and scrappie (PrPsc) conformation is associated with exosomes. Targeting of exosomes containing the normal cellular PrP could confer susceptibility of cells that do not express PrP to prion multiplication. Furthermore, exosomes bearing proteinase-K resistant PrPsc are infectious, suggesting a model in which exosomes secreted by infected cells could serve as vehicles for propagation of prions. Thus, cells may exploit the nature of endosome-derived exosomes to communicate with each other in normal and pathological situations, providing for a novel route of cell-to-cell communication and therefore of pathogen transmission. These findings open the possibility that methods to interfere with trafficking of such unconventional pathogens could be envisioned from insights on the mechanisms involved in exosome formation, secretion and targeting.     

Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins

OBJECTIVE: Exosomes are membrane vesicles of endosomal origin that are distinct from apoptotic bodies and are thought to represent an acellular mechanism for antigen transfer to classic antigen-presenting cells, as well as for direct antigen presentation with the capacity to induce immune response or tolerance. Nevertheless, it is not known whether exosomes are involved in the induction or regulation of immune responses against intracellular autoantigens that characterize autoimmune diseases. Exosomes have been shown to be secreted by several types of cells, whereas studies of non-neoplastic epithelial cells are lacking. This study was undertaken to investigate the capacity of non-neoplastic salivary gland epithelial cells (SGECs) to release exosomes, and to determine whether epithelial exosomes contain RNPs, which are major autoantigens in systemic rheumatic diseases. METHODS: Exosomes were isolated by ultracentrifugation from culture supernatants of 26 non-neoplastic SGEC lines established from patients with various rheumatic disorders. They were analyzed by electron microscopy, immunoblotting, or immunoprecipitation. RESULTS: All SGEC lines were found to release comparable and significant amounts of exosomes. Similar to other cell systems, exosome secretion was constitutive and was unrelated to activation or apoptotic processes. SGEC-derived exosomes were found to contain the autoantigenic Ro/SSA, La/SSB, and Sm RNPs, as well as epithelial-specific cytokeratins. CONCLUSION: SGECs constitutively secrete exosomes that contain the major autoantigens Ro/SSA, La/SSB, and Sm. This mechanism may represent a pathway whereby intracellular autoantigens are presented to the immune system with an immunogenic or tolerogenic outcome.     

Emerging role of engineered exosomes in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease worldwide.NAFLD comprises a continuum of liver abnormalities from nonalcoholic fatty liver to nonalcoholic steatohepatitis,and can even lead to cirrhosis and liver cancer.However,a well-established treatment for NAFLD has yet to be identified.Exosomes have become an ideal drug delivery tool because of their high transmissibility,low immunogenicity,easy accessibility and targeting.Exosomes with specific modifications...     

肝星状细胞在血吸虫病肝纤维化形成及调控中的作用

肝星状细胞(hepatic stellate cell,HSC)是肝脏组织的一种间质细胞,具有多种生理功能,对肝纤维化的形成与转归起到关键作用.HSC同样在血吸虫病肝纤维化形成及其调节中起到重要作用.该文就HSC的生物学特性、活化及其在血吸虫病肝纤维化中的作用作一综述.