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Human adipose stem cell-derived extracellular nanovesicles for treatment of chronic liver fibrosis.

人脂肪干细胞来源的细胞外纳米囊泡用于治疗慢性肝纤维化。

  • 影响因子:7.82
  • DOI:10.1016/j.jconrel.2020.01.042
  • 作者列表:"Han HS","Lee H","You D","Nguyen VQ","Song DG","Oh BH","Shin S","Choi JS","Kim JD","Pan CH","Jo DG","Cho YW","Choi KY","Park JH
  • 发表时间:2020-01-22
Abstract

:Liver fibrosis is an excessive wound healing process that occurs in response to liver damage depending on underlying aetiologies. Currently, there are no effective therapies and FDA-approved therapeutics for the treatment of liver fibrosis except liver transplantation. Multipotent adipose-derived stem cells (ADSCs) have received significant attention as regenerative medicine for liver fibrosis owing to their advantages over stem cells with other origins. However, intrinsic limitations of stem cell therapies, such as cellular rejection and tumor formation, have impeded clinical applications of the ADSC-based liver therapeutics. To overcome these problems, the extracellular nanovesicles (ENVs) responsible for the therapeutic effect of ADSCs (A-ENVs) have shown considerable promise as cell-free therapeutics for liver diseases. However, A-ENVs have not been used for the treatment of intractable chronic liver diseases including liver fibrosis and cirrhosis. Therefore, in this study, we investigated the in vitro and in vivo antifibrotic efficacy of A-ENVs in thioacetamide-induced liver fibrosis models. A-ENVs significantly downregulated the expression of fibrogenic markers, such as matrix metalloproteinase-2, collagen-1, and alpha-smooth muscle actin. The systemic administration of A-ENVs led to high accumulation in fibrotic liver tissue and the restoration of liver functionality in liver fibrosis models through a marked reduction in α-SMA and collagen deposition. These results demonstrate the significant potential of A-ENVs for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases.

摘要

: 肝纤维化是一种过度的伤口愈合过程,其发生是对肝损伤的反应,取决于潜在的病因。目前,除肝移植外,尚无有效的治疗方法和 FDA 批准的治疗方法用于治疗肝纤维化。多能脂肪干细胞 (ADSCs) 由于其优于其他来源的干细胞,作为肝纤维化的再生医学受到了极大的关注。然而,干细胞治疗的内在局限性,如细胞排斥和肿瘤形成,阻碍了基于 ADSC 的肝脏治疗的临床应用。为了克服这些问题,负责 ADSCs 治疗作用的细胞外纳米囊泡 (ENVs) (A-ENVs) 已经显示出作为肝脏疾病的无细胞治疗药物的可观前景。然而,A-ENVs 尚未用于包括肝纤维化和肝硬化在内的顽固性慢性肝病的治疗。因此,在本研究中,我们在硫代乙酰胺诱导的肝纤维化模型中研究了 A-ENVs 的体内外抗纤维化疗效。A-ENVs 显著下调纤维化标志物的表达,如基质 metalloproteinase-2 、胶原-1 和 α-平滑肌肌动蛋白。A-ENVs 的全身给药导致纤维化肝组织的高蓄积,并通过 α-SMA 和胶原沉积的显著减少恢复肝纤维化模型的肝脏功能。这些结果证明了 A-ENVs 作为基于细胞外纳米囊泡的治疗药物在治疗肝纤维化和可能的其他难治性慢性肝病中的显着潜力。

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DOI:10.1111/apt.15639
作者列表:["Moon AM","Jiang Y","Rogal SS","Tapper EB","Lieber SR","Barritt AS 4th"]

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翻译标题与摘要 下载文献
影响因子:3.87
发表时间:2020-02-01
DOI:10.1111/liv.14321
作者列表:["Chen VL","Chen Y","Du X","Handelman SK","Speliotes EK"]

METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

翻译标题与摘要 下载文献
影响因子:2.57
发表时间:2020-02-01
DOI:10.1111/eci.13198
作者列表:["Li H","Wieser A","Zhang J","Liss I","Markwardt D","Hornung R","Neumann-Cip AC","Mayerle J","Gerbes A","Steib CJ"]

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