Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome.
Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome.
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DOI：
10.1002/hep.32173
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Dong PDS
中科院分区：
文献类型：
--
作者：
Zhao C;Lancman JJ;Yang Y;Gates KP;Cao D;Barske L;Matalonga J;Pan X;He J;Graves A;Huisken J;Chen C;Dong PDS
Alagille综合征（ALGS）是一种由Notch配体基因JAGGED 1突变引起的先天性疾病，导致新生儿肝内胆管（IHD）细胞丢失和胆汁淤积。胆汁淤积在某些ALGS患者中可以消退，表明IHD细胞再生。然而，驱动IHD细胞再生的机制仍然不清楚。在这里，我们表明，胆汁淤积由于IHD细胞的发育损失，可以始终在斑马鱼与化合物jagged 1b和jagged 2b突变或敲除phenocopied。利用幼年斑马鱼中Jagged敲低的瞬时性，我们发现Jagged表达的恢复通过Notch依赖性机制导致IHD细胞的稳健再生。将多谱系追踪策略与全肝3D成像相结合，我们证明了肝外胆管（EHD）是多能祖细胞的主要来源，这些祖细胞有助于IHD细胞的再生，但不促进其发育。肝细胞向IHD细胞转分化是可能的，但很少检测到。EHD中的祖细胞增殖并迁移到肝脏中，Notch信号丢失，如果Notch信号增加，则分化为IHD细胞。组织特异性镶嵌分析与诱导显性负FGF受体表明，FGF信号从周围的间充质细胞保持这种肝外生态位，直接防止过早分化和分配的EHD祖细胞的肝脏。事实上，成年小鼠EHD类器官的转录谱和功能分析揭示了它们相对于IHD类器官的独特分化和增殖潜力。我们的数据表明，IHD细胞再生后恢复Jag/Notch信号，从多能祖细胞来源于FGF依赖性肝外干细胞龛。我们认为，如果Jagged/Notch信号增强，通过正常的随机变异，基因治疗，或Notch激动剂，ALGS患者的IHD细胞的再生可能会增强。
Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene, JAGGED1, leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain ALGS patients, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown. Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells via a Notch-dependent mechanism. Combining multiple lineage tracing strategies with whole liver 3D-imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte-to-IHD cell transdifferentiation is possible, but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue-specific mosaic analysis with an inducible dominant-negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids. Our data show that IHD cells regenerate upon resumption of Jag/Notch signaling, from multipotent progenitors originating from an Fgf-dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, via normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in ALGS patients may be enhanced.
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DOI：
10.1126/science.aba4767
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fabian P;Tseng KC;Smeeton J;Lancman JJ;Dong PDS;Cerny R;Crump JG
通讯作者：
Crump JG
影响因子：
7.7
作者：
Hockman, Dorik;Burns, Alan J.;Baker, Clare V. H.
通讯作者：
Baker, Clare V. H.
影响因子：
--
作者：
Binshtok U;Sprinzak D
通讯作者：
Sprinzak D
影响因子：
13.5
作者：
Emerick, KM;Rand, EB;Piccoli, DA
通讯作者：
Piccoli, DA
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi