Reconstruction of the Hepatic Microenvironment and Pathological Changes Underlying Type II Diabetes through Single-Cell RNA Sequencing.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.99176
Chia-Yen Dai, Ying-Ming Tsai, Chao-Yuan Chang, Hung-Pei Tsai, Kuan-Li Wu, Yu-Yuan Wu, Ling-Yu Wu, Shu-Fang Jian, Pei-Hsun Tsai, Chai-Tung Ong, Chien-Hui Sun, Ya-Ling Hsu
{"title":"Reconstruction of the Hepatic Microenvironment and Pathological Changes Underlying Type II Diabetes through Single-Cell RNA Sequencing.","authors":"Chia-Yen Dai, Ying-Ming Tsai, Chao-Yuan Chang, Hung-Pei Tsai, Kuan-Li Wu, Yu-Yuan Wu, Ling-Yu Wu, Shu-Fang Jian, Pei-Hsun Tsai, Chai-Tung Ong, Chien-Hui Sun, Ya-Ling Hsu","doi":"10.7150/ijbs.99176","DOIUrl":null,"url":null,"abstract":"<p><p>The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise. Therefore, it has become a major concern health issue worldwide. T2DM leads to various complications, including metabolic-associated fatty liver disease (MAFLD). However, comprehensive studies on MAFLD as a diabetic complication at different stages are still lacking. Using advanced single-cell RNA-seq technology, we explored changes of livers in two T2DM murine models. Our findings revealed that increase activation of hepatic stellate cells (HSCs) exacerbated the development of MAFLD to steatohepatitis by upregulating transforming growth factor β1 induced transcript 1 (<i>Tgfb1i1</i>). Upregulated thioredoxin-interacting protein (<i>Txnip</i>) contributed to hepatocyte damage by impairing reactive oxygen species clearance. Additionally, the capillarization of liver sinusoidal endothelial cells correlated with <i>Fabp4</i> overexpression in endothelial cells. A novel subset of Kupffer cells (KCs) that expressed <i>Cd36</i> exhibited an activated phenotype, potentially participating in inflammation in the liver of diabetic mice. Furthermore, ligand-receptor pair analysis indicated that activated HSCs interacted with hepatocytes or KCs through <i>Thbs2</i> and <i>Lamb2</i> in late-stage diseases. The reduction in cell-cell interactions within hepatocytes in diabetic mice, reflects that the mechanisms regulating liver homeostasis is disrupted. This research underscores the importance of dynamics in diabetic MAFLD, and provides new insights for targeted therapies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528452/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.99176","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise. Therefore, it has become a major concern health issue worldwide. T2DM leads to various complications, including metabolic-associated fatty liver disease (MAFLD). However, comprehensive studies on MAFLD as a diabetic complication at different stages are still lacking. Using advanced single-cell RNA-seq technology, we explored changes of livers in two T2DM murine models. Our findings revealed that increase activation of hepatic stellate cells (HSCs) exacerbated the development of MAFLD to steatohepatitis by upregulating transforming growth factor β1 induced transcript 1 (Tgfb1i1). Upregulated thioredoxin-interacting protein (Txnip) contributed to hepatocyte damage by impairing reactive oxygen species clearance. Additionally, the capillarization of liver sinusoidal endothelial cells correlated with Fabp4 overexpression in endothelial cells. A novel subset of Kupffer cells (KCs) that expressed Cd36 exhibited an activated phenotype, potentially participating in inflammation in the liver of diabetic mice. Furthermore, ligand-receptor pair analysis indicated that activated HSCs interacted with hepatocytes or KCs through Thbs2 and Lamb2 in late-stage diseases. The reduction in cell-cell interactions within hepatocytes in diabetic mice, reflects that the mechanisms regulating liver homeostasis is disrupted. This research underscores the importance of dynamics in diabetic MAFLD, and provides new insights for targeted therapies.

通过单细胞 RNA 测序重建 II 型糖尿病的肝脏微环境和病理变化
全球 2 型糖尿病(T2DM)的发病率持续上升。因此,它已成为全球关注的主要健康问题。T2DM 会导致各种并发症,包括代谢相关性脂肪肝(MAFLD)。然而,目前还缺乏对代谢相关性脂肪肝作为糖尿病并发症在不同阶段的全面研究。我们利用先进的单细胞 RNA-seq 技术探讨了两种 T2DM 小鼠模型肝脏的变化。我们的研究结果表明,肝星状细胞(HSCs)的活化增加通过上调转化生长因子β1诱导转录本1(Tgfb1i1),加剧了MAFLD向脂肪性肝炎的发展。上调的硫氧还蛋白相互作用蛋白(Txnip)通过影响活性氧的清除而导致肝细胞损伤。此外,肝窦内皮细胞的毛细血管化与内皮细胞中Fabp4的过度表达有关。表达 Cd36 的 Kupffer 细胞(KCs)新亚群表现出活化表型,可能参与了糖尿病小鼠肝脏的炎症反应。此外,配体-受体配对分析表明,在疾病晚期,活化的造血干细胞通过 Thbs2 和 Lamb2 与肝细胞或 KCs 相互作用。糖尿病小鼠肝细胞内的细胞-细胞相互作用减少,反映出调节肝脏平衡的机制被破坏。这项研究强调了动态变化在糖尿病 MAFLD 中的重要性,并为靶向疗法提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信