肌成纤维细胞
类有机物
病理
纤维化
肝星状细胞
生物
发病机制
先天性肝纤维化
肝纤维化
细胞生物学
癌症研究
医学
肝硬化
内科学
门脉高压
作者
Yuan Guan,Annika Enejder,Meiyue Wang,Zhuoqing Fang,Lu Cui,Shih-Yu Chen,Jingxiao Wang,Yalun Tan,Manhong Wu,Xinyu Chen,Patrik Johansson,Issra Osman,Koshi Kunimoto,Pierre Russo,Sarah C. Heilshorn,Gary Peltz
标识
DOI:10.1038/s41467-021-26410-9
摘要
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.
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