Human hepatic organoids for the analysis of human genetic diseases

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

doi:10.1172/jci.insight.94954

Cited by 184 publications

(219 citation statements)

References 61 publications

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“…Recent advances in the stem cell field have successfully demonstrated the generation of miniaturized 3D organ‐like structures, so‐called organoids, from human PSCs. By taking advantage of the self‐organization capacity of PSCs, together with specific differentiation signals, organoids representing distinct organs, such as lung, liver, kidney, stomach, pancreas, intestine, and colon, could be generated. The generation of brain organoids that correspond to different parts of brain, such as cerebral cortex, optic cups, hippocampus, pituitary gland, and cerebellum, has been also described.…”

Section: Introductionmentioning

confidence: 99%

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

et al. 2020

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Recent studies have demonstrated the generation of midbrain-like organoids (MOs) from human pluripotent stem cells. However, the low efficiency of MO generation and the relatively immature and heterogeneous structures of the MOs hinder the translation of these organoids from the bench to the clinic. Here we describe the robust generation of MOs with homogeneous distribution of midbrain dopaminergic (mDA) neurons. Our MOs contain not only mDA neurons but also other neuronal subtypes as well as functional glial cells, including astrocytes and oligodendrocytes. Furthermore, our MOs exhibit mDA neuron-specific cell death upon treatment with 1-methyl-4-phenyl-1,-2,3,6-tetrahydropyridine, indicating that MOs could be a proper human model system for studying the in vivo pathology of Parkinson's disease (PD). Our optimized conditions for producing homogeneous and mature MOs might provide an advanced patientspecific platform for in vitro disease modeling as well as for drug screening for PD.

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Section: Introductionmentioning

confidence: 99%

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

et al. 2020

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“…Apart from co-culture of different cell types as a starting point for the generation of liver organoids, other studies have shown how to start with homogeneous cell populations to obtain complex organoids. Since 2017, two different protocols were published using this approach to produce hPSC-derived liver organoids constituted by hepatocytes and cholangiocytes [90,91]. Both studies started with differentiation of hPSCs into hepatoblasts, but they diverge not only in the approach to get to that point, but also in the way they generate liver organoids.…”

Section: Production Of Liver Organoids From Human Pluripotent Stem Cellsmentioning

confidence: 99%

“…To understand liver disease mechanisms at the organ level, at least two different studies have been published studying genetic diseases in hPSC-derived liver organoids. Guan and colleagues used patient-specific hPSCs to model Alagille Syndrome (ALGS) and Tetralogy of Fallotthis (TOF) genetic disorders [90]. Firstly, they generated liver organoids from hPSCs reprogrammed from ALGS patients, where in contrast to healthy organoids, mature hepatocytes were developed, but cholangiocytes and bile ductular structure development was impaired.…”

Section: Disease Modelingmentioning

confidence: 99%

“…It is important to note that the cell composition of liver organoids can be of extreme importance when modeling liver diseases. In the examples above, it is possible to understand that given the biliary deficiencies in ALGS and TOF, the presence of cholangiocytes within these organoids it is an essential requirement [90]; similarly, given the characteristic fibrosis of steatohepatitis, HSCs should also be present [92]. Obviously, increasing the complexity of the model system will result in better recreating liver function, and it may even expose the role of the different hepatic cellular components in disease development.…”

Section: Disease Modelingmentioning

confidence: 99%

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Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

Cotovio

Fernandes

2020

Bioengineering

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Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

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“…These studies concurrently demonstrated a proof of concept for gene replacement therapy for future clinical translation [73]. More recently, in vitro organoid models of other monogenic disorders such as Alagille syndrome [74], and retinitis pigmentosa [75] have been generated, which are reviewed more extensively elsewhere [76]. cell-based therapies have the potential to alleviate symptoms or possibly cure these conditions by replacing damaged or lost cells.…”

Section: (A) Disease Modellingmentioning

confidence: 99%

Three-dimensional cell culture: from evolution to revolution

Alhaque

Themis

Rashidi

2018

Phil. Trans. R. Soc. B

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Recent advances in the isolation of tissue-resident adult stem cells and the identification of inductive factors that efficiently direct differentiation of human pluripotent stem cells along specific lineages have facilitated the development of high-fidelity modelling of several tissues Many of the novel approaches have employed self-organizing three-dimensional (3D) culturing of organoids, which offer several advantages over conventional two-dimensional platforms. Organoid technologies hold great promise for modelling diseases and predicting the outcome of drug responses Here, we outline the historical background and some of the recent advances in the field of three-dimensional organoids. We also highlight some of the current limitations of these systems and discuss potential avenues to further benefit biological research using three-dimensional modelling technologies.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.

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Human hepatic organoids for the analysis of human genetic diseases

Cited by 184 publications

References 61 publications

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications

Three-dimensional cell culture: from evolution to revolution

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