A human multi-lineage hepatic organoid model for liver fibrosis.
A human multi-lineage hepatic organoid model for liver fibrosis.
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DOI：
10.1038/s41467-021-26410-9
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发表时间：
2021-10-22
影响因子：
16.6
通讯作者：
Peltz G
中科院分区：
文献类型：
--
作者：
Guan Y;Enejder A;Wang M;Fang Z;Cui L;Chen SY;Wang J;Tan Y;Wu M;Chen X;Johansson PK;Osman I;Kunimoto K;Russo P;Heilshorn SC;Peltz G
为了研究先天性肝纤维化的发病机制，人类肝类器官被改造成表达常染色体隐性多囊肾病（ARPKD）最常见的致病突变。本研究表明，这些肝类器官仅在21天内就出现了ARPKD肝脏病理的关键特征（胆管异常和纤维化）。ARPKD突变增加了肝类器官中胶原丰度和厚胶原纤维的产生，这反映了ARPKD肝组织病理。转录组学和其他分析表明，ARPKD突变产生的胆管细胞tgf - β通路激活增加，这积极参与刺激肌成纤维细胞形成胶原纤维。生成胶原的肌成纤维细胞也有扩增，PDGFRB蛋白表达显著增加，STAT3信号通路激活。此外，ARPKD类器官肌成纤维细胞的转录组与常见的肝纤维化形式相似。当用PDGFRB抑制剂治疗ARPKD类器官时，观察到的抗纤维化作用证实了PDGFRB通路的参与。除了提供对先天性（可能获得性）肝纤维化发病机制的深入了解外，ARPKD类器官还可用于测试潜在抗纤维化疗法的抗纤维化疗效。常染色体隐性多囊肾病（ARPKD）是一种遗传性疾病，与肾脏和肝脏病理相关，包括肝纤维化。在这里，作者开发并表征了具有ARPKD突变的人类肝类器官，并发现它们表现出包括纤维化在内的病理方面。
To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFβ pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies. Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder which is associated with kidney and liver pathology, including liver fibrosis. Here the authors develop and characterize human liver organoids with a ARPKD mutation, and find that they show aspects of the pathology, including fibrosis.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
5.8
作者：
Arganda-Carreras, Ignacio;Kaynig, Verena;Seung, H. Sebastian
通讯作者：
Seung, H. Sebastian
影响因子：
3.7
作者：
Finck, Rachel;Simonds, Erin F.;Jager, Astraea;Krishnaswamy, Smita;Sachs, Karen;Fantl, Wendy;Pe'er, Dana;Nolan, Garry P.;Bendall, Sean C.
通讯作者：
Bendall, Sean C.
影响因子：
16.1
作者：
Higashi T;Friedman SL;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
2.6
作者：
Bergmann C
通讯作者：
Bergmann C