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Human hepatic organoids for the analysis of human genetic diseases
Yuan Guan, … , Julien Sage, Gary Peltz
Yuan Guan, … , Julien Sage, Gary Peltz
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94954. https://doi.org/10.1172/jci.insight.94954.
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Resource and Technical Advance Genetics Hepatology

Human hepatic organoids for the analysis of human genetic diseases

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Abstract

We developed an in vitro model system where induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional human hepatic organoids (HOs) through stages that resemble human liver during its embryonic development. The HOs consist of hepatocytes, and cholangiocytes, which are organized into epithelia that surround the lumina of bile duct–like structures. The organoids provide a potentially new model for liver regenerative processes, and were used to characterize the effect of different JAG1 mutations that cause: (a) Alagille syndrome (ALGS), a genetic disorder where NOTCH signaling pathway mutations impair bile duct formation, which has substantial variability in its associated clinical features; and (b) Tetralogy of Fallot (TOF), which is the most common form of a complex congenital heart disease, and is associated with several different heritable disorders. Our results demonstrate how an iPSC-based organoid system can be used with genome editing technologies to characterize the pathogenetic effect of human genetic disease-causing mutations.

Authors

Yuan Guan, Dan Xu, Phillip M. Garfin, Ursula Ehmer, Melissa Hurwitz, Greg Enns, Sara Michie, Manhong Wu, Ming Zheng, Toshihiko Nishimura, Julien Sage, Gary Peltz

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Figure 1

Generation of HOs from iPSCs.

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Generation of HOs from iPSCs.
(A) A schematic representation of the in v...
(A) A schematic representation of the in vitro culture system and the growth factors used to direct the differentiation of iPSCs into HO1s. Then, the cells in a HO1 are dissociated, and (B and C) bright-field and immunostaining images taken on day 0 (iPSCs), day 3 (definitive endoderm, EN), day 6 (foregut, FG), day 9 (hepatoblast, HB), day 20 (HO1), and day 62 (HO2) show the morphological and cell marker changes that occur during the development of HOs. The arrows indicate where duct-like structures are located. (D) H&E staining shows the appearance of 3 different types of HO1. (E and F) Immunostained sections prepared from day 50 parenchymal, ductal, or mixed organoids show the pattern of expression of hepatocyte (ALB, CK8, A1AT), cholangiocyte (CK19), or proliferation (Ki67) markers. Scale bars: 50 μm.

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