Generation of uniform liver spheroids from human pluripotent stem cells for imaging-based drug toxicity analysis

Lee, Gyunggyu; Kim, Hye Min; Park, Ji Young; Kim, Gyeongmin; Han, Jiyou; Chung, Seok; Yang, Ji; Jeon, Jang Su; Woo, Dong Hun; Han, Choongseong; Kim, Sang Kyum; Park, Han-Jin; Kim, Jong Hoon

doi:10.1016/j.biomaterials.2020.120529

Cited by 48 publications

(41 citation statements)

References 54 publications

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“…In contrast, others have shown that spheroids of iPSC-heps were capable of albumin production, urea synthesis, glycogen storage and gene expression of drug-metabolizing enzymes ( CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT2B7 ). However, again, levels remained far below those of pHHs [ 101 ]. A very recent study compared 2D and 3D cultured iPSC-heps with pHHs cultured in 2D and 3D spheroids.…”

Section: Three-dimensional Culture Models For Human Hepatocytesmentioning

confidence: 99%

“…Interestingly, iPSC-hep spheroids were more sensitive to a set of 24 hepatotoxic compounds than HepG2 spheroids in one study [ 100 ], while another study showed opposite results for 10 out of 23 tested compounds [ 105 ]. When compared to pHH spheroids, IC50 values of iPSC-hep spheroids were similar in 12/15 tested hepatotoxic compounds [ 101 ]. In another study, the authors tested a set of seven hepatotoxic compounds and found that pHHs generally displayed higher sensitivity [ 102 ].…”

Section: Three-dimensional Culture Models For Human Hepatocytesmentioning

confidence: 99%

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Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro

Kammerer

2021

IJMS

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Drug-induced liver injury (DILI) is the major reason for failures in drug development and withdrawal of approved drugs from the market. Two-dimensional cultures of hepatocytes often fail to reliably predict DILI: hepatoma cell lines such as HepG2 do not reflect important primary-like hepatic properties and primary human hepatocytes (pHHs) dedifferentiate quickly in vitro and are, therefore, not suitable for long-term toxicity studies. More predictive liver in vitro models are urgently required in drug development and compound safety evaluation. This review discusses available human hepatic cell types for in vitro toxicology analysis and their usage in established and emerging three-dimensional (3D) culture systems. Generally, 3D cultures maintain or improve primary hepatic functions (including expression of drug-metabolizing enzymes) of different liver cells for several weeks of culture, thus allowing long-term and repeated-dose toxicity studies. Spheroid cultures of pHHs have been comprehensively tested, but also other cell types such as HepaRG benefit from 3D culture systems. Emerging 3D culture techniques include usage of induced pluripotent stem-cell-derived hepatocytes and primary-like upcyte cells, as well as advanced culture techniques such as microfluidic liver-on-a-chip models. In-depth characterization of existing and emerging 3D hepatocyte technologies is indispensable for successful implementation of such systems in toxicological analysis.

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Section: Three-dimensional Culture Models For Human Hepatocytesmentioning

confidence: 99%

Section: Three-dimensional Culture Models For Human Hepatocytesmentioning

confidence: 99%

Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro

Kammerer

2021

IJMS

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“…This problem hinders their applications in disease modeling and drug development. Currently, the differentiation of hepatic progenitors is mediated by HGF, oncostatin M (Prodanov et al, 2016), and dexamethasone, but the resultant hepatocytes exhibit fetal liver features (Baxter et al, 2015), such as the expression of fetal marker alpha-fetoprotein (Lucendo-Villarin et al, 2020) and lower activity of CYP3A4 than primary hepatocytes (Lee et al, 2021).…”

Section: Immaturitymentioning

confidence: 99%

“…To overcome this issue, researchers have fabricated microwells to control spheroid size and uniformity (Takebe et al, 2017). Silicone microwells were recently used to generate uniform hepatocyte spheroids from human PSCs (Lee et al, 2021). These spheroids were more sensitive to liver toxins than 2D hepatocytes in image-based testing.…”

Section: Heterogeneitymentioning

confidence: 99%

Challenges for the Applications of Human Pluripotent Stem Cell-Derived Liver Organoids

Chang

Bogacheva

Lou

2021

Front. Cell Dev. Biol.

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The current organoid culture systems allow pluripotent and adult stem cells to self-organize to form three-dimensional (3D) structures that provide a faithful recapitulation of the architecture and function of in vivo organs. In particular, human pluripotent stem cell-derived liver organoids (PSC-LOs) can be used in regenerative medicine and preclinical applications, such as disease modeling and drug discovery. New bioengineering tools, such as microfluidics, biomaterial scaffolds, and 3D bioprinting, are combined with organoid technologies to increase the efficiency of hepatic differentiation and enhance the functional maturity of human PSC-LOs by precise control of cellular microenvironment. Long-term stabilization of hepatocellular functions of in vitro liver organoids requires the combination of hepatic endodermal, endothelial, and mesenchymal cells. To improve the biological function and scalability of human PSC-LOs, bioengineering methods have been used to identify diverse and zonal hepatocyte populations in liver organoids for capturing heterogeneous pathologies. Therefore, constructing engineered liver organoids generated from human PSCs will be an extremely versatile tool in in vitro disease models and regenerative medicine in future. In this review, we aim to discuss the recent advances in bioengineering technologies in liver organoid culture systems that provide a timely and necessary study to model disease pathology and support drug discovery in vitro and to generate cell therapy products for transplantation.

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“…Specifically, hiPSC-derived liver cells have the potential to reflect the individual variability in drug metabolism capacities, which overcomes the limitations of using a single PHH line for drug toxicity testing [ 81 ]. Moreover, by coupling with high-throughput screening systems, various platforms that support the quick examination of thousands of small molecules have been established using hiPSC-derived HLCs [ 47 , 82 ] or liver organoids [ 83 , 84 ]. In a recent breakthrough, Shinozawa et al developed a high-throughput screening platform to test drug toxicity with dual readouts, including viability and cholestatic function, based on an organoid containing a functional bile canaliculi-like structure [ 84 ].…”

Section: Applications Of Hpsc-derived Hepatic Lineages In Pharmaceutical Discoverymentioning

confidence: 99%

Human Pluripotent Stem Cell-Derived Hepatocyte-Like Cells and Organoids for Liver Disease and Therapy

Xia

Plummer

et al. 2021

IJMS

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Liver disease is a global health issue that has caused an economic burden worldwide. Organ transplantation is the only effective therapy for end-stage liver disease; however, it has been hampered by a shortage of donors. Human pluripotent stem cells (hPSCs) have been widely used for studying liver biology and pathology as well as facilitating the development of alternative therapies. hPSCs can differentiate into multiple types of cells, which enables the generation of various models that can be applied to investigate and recapitulate a range of biological activities in vitro. Here, we summarize the recent development of hPSC-derived hepatocytes and their applications in disease modeling, cell therapy, and drug discovery. We also discuss the advantages and limitations of these applications and critical challenges for further development.

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Generation of uniform liver spheroids from human pluripotent stem cells for imaging-based drug toxicity analysis

Cited by 48 publications

References 54 publications

Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro

Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro

Challenges for the Applications of Human Pluripotent Stem Cell-Derived Liver Organoids

Human Pluripotent Stem Cell-Derived Hepatocyte-Like Cells and Organoids for Liver Disease and Therapy

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