Generation of hepatobiliary organoids from human induced pluripotent stem cells

Wu, Fenfang; Wu, Di; Ren, Yong; Huang, Yuhua; Feng, Bo; Zhao, Nan; Zhang, Taotao; Chen, Xiaoni; Chen, Shangwu; Xu, Anlong

doi:10.1016/j.jhep.2018.12.028

Cited by 162 publications

(132 citation statements)

References 44 publications

(46 reference statements)

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“…Recent reports have shown that primary murine hepatocytes derived from adult livers can be maintained for a long time in a 3D organoid culture system [66][67][68]. Human liver organoids derived from human iPS cells may be established using the technique assisted by the methods for the long-term culture of primary hepatocytes [69]. Human iPS cell-derived organoids composed Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Kakinuma

Watanabe

2019

Immunological Medicine

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Results of recent studies have shown that disease models using human induced pluripotent stem (iPS) cells have recapitulated the pathophysiology of genetic liver diseases, viral hepatitis and hepatic fibrosis. The utilization of human iPS cells as a model of liver diseases has several substantial advantages compared with primary hepatocytes and cancer cell lines, such as the potential for unlimited expansion and similarity of biological characteristics to normal liver cells. In this review, we have focused on modeling liver diseases using human iPS cells and discussed the experimental evidence that supports the utility of such disease models, including that in our recent studies. Genetically modified or patient-derived human iPS cells can mimic congenital liver disease phenotypes. Human iPS-derived hepatic cells can be infected with the hepatitis viruses. The co-culture of human iPS-derived hepatocytes and mesenchyme partially mimics the process of liver fibrosis. Human iPS cell-derived hepatic cells and the co-culture system of such cells will contribute to the progress of studies on the pathophysiology of genetic and non-genetic liver diseases and development of novel therapeutic strategies for treating liver diseases.

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Section: Resultsmentioning

confidence: 99%

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Kakinuma

Watanabe

2019

Immunological Medicine

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“…69 In a subsequent study by an independent group, HCC and CCA tumouroids were established from patient-derived needle biopsies with around a 30% success rate, and could be maintained in culture for up to 32 weeks 70 Through the use of the needle biopsy sample acquisition protocol, non-tumoural liver tissue was also collected and used to generate patientderived liver organoids for normalisation of data generated from the corresponding patient's tumouroid. 60 Most liver tumouroids established to date closely resemble the original tumour biopsy in terms of growth pattern, differentiation grade, expression of HCC-specific markers, genomic alterations, and ability to form tumours in xenograft models. 69,70 This represents a difference from 2D cancer cell lines, which tend to lose their original patient-specific genetic signature and acquire additional mutations, possibly because of the need to adapt to a non-physiologic environment which lacks signalling from surrounding stromal tissue.…”

Section: Organoids From Pluripotent Stem Cellsmentioning

confidence: 99%

“…59 iPSCs can also be used to generate hepatobiliary organoids by inducing endodermal and mesodermal differentiation in a modified media. 60 Some reports suggest that genetic and epigenetic aberrations may occur during the derivation and reprogramming processes, [61][62][63] including the development of chromosomal abnormalities 64 , ''de novo" copy number variations, 65 and point mutations in protein-coding regions. 66 Such changes may complicate their use in regenerative medicine; 67 however, novel advances in gene editing technologies and the establishment of iPSCs may circumvent these problems.…”

Section: Organoids From Pluripotent Stem Cellsmentioning

confidence: 99%

Novel patient-derived preclinical models of liver cancer

Bresnahan

Ramadori

Heikenwälder

et al. 2020

Journal of Hepatology

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Preclinical models of cancer based on the use of human cancer cell lines and mouse models have enabled discoveries that have been successfully translated into patients. And yet the majority of clinical trials fail, emphasising the urgent need to improve preclinical research to better interrogate the potential efficacy of each therapy and the patient population most likely to benefit. This is particularly important for liver malignancies, which lack highly efficient treatments and account for hundreds of thousands of deaths around the globe. Given the intricate network of genetic and environmental factors that contribute to liver cancer development and progression, the identification of new druggable targets will mainly depend on establishing preclinical models that mirror the complexity of features observed in patients. The development of new 3D cell culture systems, originating from cells/tissues isolated from patients, might create new opportunities for the generation of more specific and personalised therapies. However, these systems are unable to recapitulate the tumour microenvironment and interactions with the immune system, both proven to be critical influences on therapeutic outcomes. Patient-derived xenografts, in particular with humanised mouse models, more faithfully mimic the physiology of human liver cancer but are costly and time-consuming, which can be prohibitive for personalising therapies in the setting of an aggressive malignancy. In this review, we discuss the latest advances in the development of more accurate preclinical models to better understand liver cancer biology and identify paradigm-changing therapies, stressing the importance of a bi-directional communicative flow between clinicians and researchers to establish reliable model systems and determine how best to apply them to expanding our current knowledge.

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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%

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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Generation of hepatobiliary organoids from human induced pluripotent stem cells

Cited by 162 publications

References 44 publications

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Novel patient-derived preclinical models of liver cancer

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

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