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Journal articles on the topic 'Induced-pluripotent Stem Cell-derived Hepatocytes'

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Author: Grafiati

Published: 10 December 2022

Last updated: 28 January 2023

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1

Medine, Claire N., Sebastian Greenhough, and David C. Hay. "Role of stem-cell-derived hepatic endoderm in human drug discovery." Biochemical Society Transactions 38, no. 4 (July 26, 2010): 1033–36. http://dx.doi.org/10.1042/bst0381033.

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Accurate prediction of human drug toxicity is a vital part of the drug discovery process. However, the safety evaluation process is hindered by the availability and quality of primary human liver models with which to study drug toxicity. In an attempt to overcome this limitation, research has focused on deriving human hepatocytes from a number of sources, including progenitors from fetal and adult liver, human cell lines derived from liver tumours, immortalized human hepatocytes and pluripotent stem cells. The major hurdles in developing scalable and high-fidelity human hepatocytes from hepatic cell lines and fetal and adult progenitors have been limited organ availability, homogeneous cell purification, short-term cell culture, and the rapid loss of hepatocyte phenotype and function in culture. Therefore it has been necessary to find alternative sources of human hepatocytes which circumvent these issues. The research in our group has focused on generating human hepatic endoderm from the scalable pluripotent stem cell populations, human embryonic stem cells and induced pluripotent stem cells. We have developed efficient and scalable models of human hepatocyte differentiation from these cell populations. Moreover, stem-cell-derived hepatic endoderm displays many of the functional attributes of primary human hepatocytes. Our research is now focused on developing defined culture systems and improving cell culture microenvironments in order to improve our understanding of the mechanisms regulating human liver development. This will in turn facilitate the generation of broad-range functioning hepatic endoderm in vitro. By taking these approaches, we believe that it will be possible to improve the predictive nature of our in vitro models, revolutionizing the manner in which industry measures human drug toxicity and having an impact on drug attrition.

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2

Hannoun, Zara, Clara Steichen, Noushin Dianat, Anne Weber, and Anne Dubart-Kupperschmitt. "The potential of induced pluripotent stem cell derived hepatocytes." Journal of Hepatology 65, no. 1 (July 2016): 182–99. http://dx.doi.org/10.1016/j.jhep.2016.02.025.

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3

Shi, Ying, Jiali Deng, Xiaopu Sang, Yihang Wang, Fei He, Xiaoni Chen, Anlong Xu, and Fenfang Wu. "Generation of Hepatocytes and Nonparenchymal Cell Codifferentiation System from Human-Induced Pluripotent Stem Cells." Stem Cells International 2022 (November 22, 2022): 1–18. http://dx.doi.org/10.1155/2022/3222427.

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To date, hepatocytes derived from human-induced pluripotent stem cells (hiPSC) provide a potentially unlimited resource for clinical application and drug development. However, most hiPSC-derived hepatocyte-like cells initiated differentiation from highly purified definitive endoderm, which are insufficient to accurately replicate the complex regulation of signals among multiple cells and tissues during liver organogenesis, thereby displaying an immature phenotypic and short survival time in vitro. Here, we described a protocol to achieve codifferentiation of endoderm-derived hepatocytes and mesoderm-derived nonparenchymal cells by the inclusion of BMP4 into hepatic differentiation medium, which has a beneficial effect on the hepatocyte maturation and lifespan in vitro. Our codifferentiation system suggests the important role of nonparenchymal cells in liver organogenesis. Hopefully, these hepatocytes described here provide a promising approach in the therapy of liver diseases.

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4

Iwamuro, Masaya, Javed M. Shahid, Kazuhide Yamamoto, and Naoya Kobayashi. "Prospects for Induced Pluripotent Stem Cell-Derived Hepatocytes in Cell Therapy." Cell Medicine 2, no. 1 (April 2011): 1–8. http://dx.doi.org/10.3727/215517911x575975.

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5

Mann, David A. "Human induced pluripotent stem cell-derived hepatocytes for toxicology testing." Expert Opinion on Drug Metabolism & Toxicology 11, no. 1 (November 11, 2014): 1–5. http://dx.doi.org/10.1517/17425255.2015.981523.

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6

Pradip, Arvind, Daniella Steel, Susanna Jacobsson, Gustav Holmgren, Magnus Ingelman-Sundberg, Peter Sartipy, Petter Björquist, Inger Johansson, and Josefina Edsbagge. "High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis." Stem Cells International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/2475631.

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Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevantin vitroandin vivotesting systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA). The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic) based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.

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7

Gieseck III, Richard L., Nicholas R. F. Hannan, Roque Bort, Neil A. Hanley, Rosemary A. L. Drake, Grant W. W. Cameron, Thomas A. Wynn, and Ludovic Vallier. "Maturation of Induced Pluripotent Stem Cell Derived Hepatocytes by 3D-Culture." PLoS ONE 9, no. 1 (January 22, 2014): e86372. http://dx.doi.org/10.1371/journal.pone.0086372.

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8

Takagi, Chisato, Hiroshi Yagi, Makiko Hieda, Kazuki Tajima, Taizo Hibi, Yuta Abe, Minoru Kitago, Masahiro Shinoda, Osamu Itano, and Yuko Kitagawa. "Mesenchymal Stem Cells Contribute to Hepatic Maturation of Human Induced Pluripotent Stem Cells." European Surgical Research 58, no. 1-2 (September 7, 2016): 27–39. http://dx.doi.org/10.1159/000448516.

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Background: Induced pluripotent stem cells (iPSCs) are human somatic cells that have been reprogrammed to a pluripotent state. Several methods have been used to generate hepatocyte-like cells from iPSCs. However, these hepatic cells have limited clinical application because of their immature function compared to primary hepatocytes. Mesenchymal stem cells (MSCs) have been reported to inhibit apoptosis of hepatic cells and to improve hepatic regeneration in acute liver injury. Therefore, we expected that MSCs had the potential to positively contribute to the maturation of hepatic cells. Here we demonstrate the effect of MSCs on the maturation of hepatoblasts derived from human iPSCs. Methods: MSCs were isolated from human bone marrow and cultured to 70-80% confluence. MSC-conditioned medium (MSC-CM) was collected 48 h after culture in hepatic maturation medium. Human iPSC-derived hepatoblasts were then cultured for 6 days with MSC-CM. Hepatic functions were analyzed and compared to those from cells cultured in general maturation medium. Results: Cells in both groups had a cuboidal morphology typical of hepatocytes. The proportion of Oct4-positive cells was decreased and those of albumin- and alpha-fetoprotein-positive cells were increased in the MSC-CM group. Albumin secretion and urea synthesis as well as cytochrome P450 (CYP) 3A4 activity were enhanced in the MSC-CM group. The gene expressions of some CYP enzymes were upregulated as demonstrated by RT-PCR. Conclusion: Secreted molecules from human MSCs could enhance the hepatic function of human iPSC-derived hepatocyte-like cells. Although more technological innovations are needed, MSC-CM will be useful as a novel efficient strategy for clinically relevant hepatic cell maturation.

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9

Jeong, Jaemin, Tae Hun Kim, Myounghoi Kim, Yun Kyung Jung, Kyeong Sik Kim, Sehwan Shim, Hyosun Jang, Won Il Jang, Seung Bum Lee, and Dongho Choi. "Elimination of Reprogramming Transgenes Facilitates the Differentiation of Induced Pluripotent Stem Cells into Hepatocyte-like Cells and Hepatic Organoids." Biology 11, no. 4 (March 23, 2022): 493. http://dx.doi.org/10.3390/biology11040493.

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Hepatocytes and hepatic organoids (HOs) derived from human induced pluripotent stem cells (hiPSCs) are promising cell-based therapies for liver diseases. The removal of reprogramming transgenes can affect hiPSC differentiation potential into the three germ layers but not into hepatocytes and hepatic organoids in the late developmental stage. Herein, we generated hiPSCs from normal human fibroblasts using an excisable polycistronic lentiviral vector based on the Cre recombinase-mediated removal of the loxP-flanked reprogramming cassette. Comparing the properties of transgene-carrying and transgene-free hiPSCs with the same genetic background, the pluripotent states of all hiPSCs were quite similar, as indicated by the expression of pluripotent markers, embryonic body formation, and tri-lineage differentiation in vitro. However, after in vitro differentiation into hepatocytes, transgene-free hiPSCs were superior to the transgene-residual hiPSCs. Interestingly, the generation and hepatic differentiation of human hepatic organoids (hHOs) were significantly enhanced by transgene elimination from hiPSCs, as observed by the upregulated fetal liver (CK19, SOX9, and ITGA6) and functional hepatocyte (albumin, ASGR1, HNF4α, CYP1A2, CYP3A4, and AAT) markers upon culture in differentiation media. Thus, the elimination of reprogramming transgenes facilitates hiPSC differentiation into hepatocyte-like cells and hepatic organoids with properties of liver progenitor cells. Our findings thus provide significant insights into the characteristics of iPSC-derived hepatic organoids.

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Inoue, Tomoaki, Norihiko Iwazaki, Tetsuro Araki, and Hiroko Hitotsumachi. "Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals." Current Pharmaceutical Biotechnology 21, no. 9 (June 9, 2020): 773–79. http://dx.doi.org/10.2174/1389201021666200131123524.

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Human hepatocytes are essential cell types for pharmacokinetics and the safety evaluation of pharmaceuticals. However, widely used primary hepatocytes with individual variations in liver function lose those functions rapidly in culture. Hepatic cell lines are convenient to use but have low liver functions. Human-Induced Pluripotent Stem (hiPS) cells can be expanded and potentially differentiated into any cell or tissue, including the liver. HiPS cell-derived Hepatocyte-Like Cells (hiPSHeps) are expected to be extensively used as consistent functional human hepatocytes. Many laboratories are investigating methods of using hiPS cells to differentiate hepatocytes, but the derived cells still have immature liver functions. In this paper, we describe the current uses and limitations of conventional hepatic cells, evaluating the suitability of hiPS-Heps to pharmacokinetics and the safety evaluation of pharmaceuticals, and discuss the potential future use of non-conventional non-monolayer culture methods to derive fully functional hiPS-Heps.

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11

Kulkeaw, Kasem, Alisa Tubsuwan, Nongnat Tongkrajang, and Narisara Whangviboonkij. "Generation of human liver organoids from pluripotent stem cell-derived hepatic endoderms." PeerJ 8 (October 19, 2020): e9968. http://dx.doi.org/10.7717/peerj.9968.

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Background The use of a personalized liver organoid derived from human-induced pluripotent stem cells (HuiPSCs) is advancing the use of in vitro disease models for the design of specific, effective therapies for individuals. Collecting patient peripheral blood cells for HuiPSC generation is preferable because it is less invasive; however, the capability of blood cell-derived HuiPSCs for hepatic differentiation and liver organoid formation remains uncertain. Moreover, the currently available methods for liver organoid formation require a multistep process of cell differentiation or a combination of hepatic endodermal, endothelial and mesenchymal cells, which is a major hurdle for the application of personalized liver organoids in high-throughput testing of drug toxicity and safety. To demonstrate the capability of blood cell-derived HuiPSCs for liver organoid formation without support from endothelial and mesenchymal cells. Methods The peripheral blood-derived HuiPSCs first differentiated into hepatic endoderm (HE) in two-dimensional (2D) culture on Matrigel-coated plates under hypoxia for 10 days. The HE was then collected and cultured in 3D culture using 50% Matrigel under ambient oxygen. The maturation of hepatocytes was further induced by adding hepatocyte growth medium containing HGF and oncostatin M on top of the 3D culture and incubating the culture for an additional 12–17 days. The function of the liver organoids was assessed using expression analysis of hepatocyte-specific gene and proteins. Albumin (ALB) synthesis, glycogen and lipid storage, and metabolism of indocyanine were evaluated. The spatial distribution of albumin was examined using immunofluorescence and confocal microscopy. Results CD34+ hematopoietic cell-derived HuiPSCs were capable of differentiating into definitive endoderm expressing SOX17 and FOXA2, hepatic endoderm expressing FOXA2, hepatoblasts expressing AFP and hepatocytes expressing ALB. On day 25 of the 2D culture, cells expressed SOX17, FOXA2, AFP and ALB, indicating the presence of cellular heterogeneity. In contrast, the hepatic endoderm spontaneously formed a spherical, hollow structure in a 3D culture of 50% Matrigel, whereas hepatoblasts and hepatocytes could not form. Microscopic observation showed a single layer of polygonal-shaped cells arranged in a 3D structure. The hepatic endoderm-derived organoid synthesis ALB at a higher level than the 2D culture but did not express definitive endoderm-specific SOX17, indicating the greater maturity of the hepatocytes in the liver organoids. Confocal microscopic images and quantitative ELISA confirmed albumin synthesis in the cytoplasm of the liver organoid and its secretion. Overall, 3D culture of the hepatic endoderm is a relatively fast, simple, and less laborious way to generate liver organoids from HuiPSCs that is more physiologically relevant than 2D culture.

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12

Kamimura, Ryo, Takamichi Ishii, Naoya Sasaki, Masatoshi Kajiwara, Takafumi Machimoto, Michiko Saito, Kenji Kohno, et al. "Comparative Study of Transplantation of Hepatocytes at Various Differentiation Stages into Mice with Lethal Liver Damage." Cell Transplantation 21, no. 11 (November 2012): 2351–62. http://dx.doi.org/10.3727/096368912x636957.

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Hepatocyte transplantation utilizing induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) has been expected to provide an alternative to liver transplantation. However, it remains uncertain precisely which cell type is the best suited for cell transplantation. In particular, it is unclear whether mature hepatocytes, which have sufficient liver function, or immature hepatic progenitor cells, which have a higher proliferative capacity, will provide a better outcome. The main objective of this study was to investigate the therapeutic efficacy of the transplantation of hepatocytes at various differentiation stages. We utilized transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. ESC-derived endodermal cells, fetal hepatocytes, and adult hepatocytes were transplanted into these mice with experimentally induced lethal acute liver injury caused by DT administration. The transplanted cells were marked by enhanced green fluorescent protein. We evaluated their effects on survival. At 35 days after transplantation, the survival rate of the adult hepatocyte-transplanted group (8/20, 40%) was significantly improved in comparison to that of the sham-operated group (2/25, 8%), the fetal hepatocyte-transplanted group (1/20, 5%), and the ESC-derived endodermal cell-transplanted group (0/21, 0%). The adult hepatocytes proliferated in the recipient livers and replaced a large part of their parenchyma. The transplantation of adult hepatocytes for acute liver failure significantly improved the survival rate in comparison to that of transplantation of immature cells, thus suggesting that ESCs and iPSCs should be differentiated into mature hepatocytes before cell transplantation for acute liver failure.

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13

Kuse, Yoshiki, and Hideki Taniguchi. "Present and Future Perspectives of Using Human-Induced Pluripotent Stem Cells and Organoid Against Liver Failure." Cell Transplantation 28, no. 1_suppl (December 2019): 160S—165S. http://dx.doi.org/10.1177/0963689719888459.

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Organ failure manifests severe symptoms affecting the whole body that may cause death. However, the number of organ donors is not enough for patients requiring transplantation worldwide. Illegal transplantation is also sometimes conducted. To help address this concern, primary hepatocytes are clinically transplanted in the liver. However, donor shortage and host rejection via instant blood-mediated inflammatory reactions are worrisome. Induced pluripotent stem cell-derived hepatocyte-like cells have been developed as an alternative treatment. Recently, organoid technology has been developed to investigate the pathology and mechanism of organoids in cultures. Organoids can be transplanted with vascularization and connected to host blood vessels, and functionally mature better in vivo than in vitro. Hepatic organoids improve pathology in liver disease models. In this review, we introduce induced pluripotent stem cell- and organoid-based therapies against liver diseases considering present and future perspectives.

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14

Unzu, Carmen, Marc Friedli, Alexis Bosman, Marisa E. Jaconi, Barbara E. Wildhaber, and Anne-Laure Rougemont. "Human Hepatocyte-Derived Induced Pluripotent Stem Cells: MYC Expression, Similarities to Human Germ Cell Tumors, and Safety Issues." Stem Cells International 2016 (2016): 1–16. http://dx.doi.org/10.1155/2016/4370142.

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Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogenemycshowed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such asmycmight be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stem cell-based approaches for liver metabolic diseases.

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15

Skrzypczyk, Aniela, Stephanie Kehr, Ilona Krystel, Stephan H. Bernhart, Shibashish Giri, Augustinus Bader, and Peter F. Stadler. "Noncoding RNA Transcripts during Differentiation of Induced Pluripotent Stem Cells into Hepatocytes." Stem Cells International 2018 (August 19, 2018): 1–15. http://dx.doi.org/10.1155/2018/5692840.

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Recent advances in the stem cell field allow to obtain many human tissues in vitro. However, hepatic differentiation of induced pluripotent stem cells (iPSCs) still remains challenging. Hepatocyte-like cells (HLCs) obtained after differentiation resemble more fetal liver hepatocytes. MicroRNAs (miRNA) play an important role in the differentiation process. Here, we analysed noncoding RNA profiles from the last stages of differentiation and compare them to hepatocytes. Our results show that HLCs maintain an epithelial character and express miRNA which can block hepatocyte maturation by inhibiting the epithelial-mesenchymal transition (EMT). Additionally, we identified differentially expressed small nucleolar RNAs (snoRNAs) and discovered novel noncoding RNA (ncRNA) genes.

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Romano, Marco, Raul Elgueta, Daniel McCluskey, Ana Maria Ortega-Prieto, Emilie Stolarczyk, Francesco Dazzi, Baltasar Lucendo-Villarin, et al. "Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation In Vitro through Tryptophan Starvation." Cells 11, no. 1 (December 22, 2021): 24. http://dx.doi.org/10.3390/cells11010024.

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Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate in vitro the immunological properties of human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs). These cells expressed MHC class I molecules while they lacked MHC class II and co-stimulatory molecules, such as CD80 and CD86. Following stimulation with IFN-γ, HLCs upregulated CD40, PD-L1 and MHC class I molecules. When co-cultured with allogeneic T cells, HLCs did not induce T cell proliferation; furthermore, when T cells were stimulated via αCD3/CD28 beads, HLCs inhibited their proliferation via IDO1 and tryptophan deprivation. These results demonstrate that PSC-derived HLCs possess immunoregulatory functions, at least in vitro.

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Zahmatkesh, Ensieh, Mohammad Hossein Ghanian, Ibrahim Zarkesh, Zahra Farzaneh, Majid Halvaei, Zahra Heydari, Farideh Moeinvaziri, et al. "Tissue-Specific Microparticles Improve Organoid Microenvironment for Efficient Maturation of Pluripotent Stem-Cell-Derived Hepatocytes." Cells 10, no. 6 (May 21, 2021): 1274. http://dx.doi.org/10.3390/cells10061274.

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Liver organoids (LOs) are receiving considerable attention for their potential use in drug screening, disease modeling, and transplantable constructs. Hepatocytes, as the key component of LOs, are isolated from the liver or differentiated from pluripotent stem cells (PSCs). PSC-derived hepatocytes are preferable because of their availability and scalability. However, efficient maturation of the PSC-derived hepatocytes towards functional units in LOs remains a challenging subject. The incorporation of cell-sized microparticles (MPs) derived from liver extracellular matrix (ECM), could provide an enriched tissue-specific microenvironment for further maturation of hepatocytes inside the LOs. In the present study, the MPs were fabricated by chemical cross-linking of a water-in-oil dispersion of digested decellularized sheep liver. These MPs were mixed with human PSC-derived hepatic endoderm, human umbilical vein endothelial cells, and mesenchymal stromal cells to produce homogenous bioengineered LOs (BLOs). This approach led to the improvement of hepatocyte-like cells in terms of gene expression and function, CYP activities, albumin secretion, and metabolism of xenobiotics. The intraperitoneal transplantation of BLOs in an acute liver injury mouse model led to an enhancement in survival rate. Furthermore, efficient hepatic maturation was demonstrated after ex ovo transplantation. In conclusion, the incorporation of cell-sized tissue-specific MPs in BLOs improved the maturation of human PSC-derived hepatocyte-like cells compared to LOs. This approach provides a versatile strategy to produce functional organoids from different tissues and offers a novel tool for biomedical applications.

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18

Kulkarni, Sakil, and David A. Rudnick. "Induced Pluripotent Stem Cell-Derived Hepatocytes and Precision Medicine in Human Liver Disease." Journal of Pediatric Gastroenterology and Nutrition 66, no. 5 (May 2018): 716–19. http://dx.doi.org/10.1097/mpg.0000000000001948.

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19

Kanamori, Tatsuyuki, Yuko Togawa Iwata, Hiroki Segawa, Tadashi Yamamuro, Kenji Kuwayama, Kenji Tsujikawa, and Hiroyuki Inoue. "Metabolism of Fentanyl and Acetylfentanyl in Human-Induced Pluripotent Stem Cell-Derived Hepatocytes." Biological & Pharmaceutical Bulletin 41, no. 1 (2018): 106–14. http://dx.doi.org/10.1248/bpb.b17-00709.

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20

Deepak, Hiraganahalli Bhaskar, Nellikalaya Shreekrishna, Zaheerbasha Sameermahmood, Niranjan Naranapur Anand, Raghotham Hulgi, Juluri Suresh, Sonal Khare, and Saravanakumar Dhakshinamoorthy. "An in vitro model of hepatic steatosis using lipid loaded induced pluripotent stem cell derived hepatocyte like cells." Journal of Biological Methods 7, no. 3 (July 22, 2020): e135. http://dx.doi.org/10.14440/jbm.2020.330.

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Hepatic steatosis is a metabolic disease, characterized by selective and progressive accumulation of lipids in liver, leading to progressive non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis. The existing in vitro models of hepatic steatosis to elucidate the molecular mechanisms behind the onset of hepatic steatosis and to profile small molecule modulators uses lipid loaded primary hepatocytes, and cell lines like HepG2. The limitation of these models includes high variability between the different donor samples, reproducibility, and translatability to physiological context. An in vitro human hepatocyte derived model that mimics the pathophysiological changes seen in hepatic steatosis may provide an alternative tool for pre-clinical drug discovery research. We report the development of an in vitro experimental model of hepatic steatosis using human induced pluripotent stem cell (iPSC) derived hepatocytes like cells (HLC), loaded with lipids. Our data suggests that HLC carry some of the functional characteristics of primary hepatocytes and are amenable for development of an in vitro steatosis model using lipid loading method. The in vitro experimental model of hepatic steatosis was further characterized using biomarker analysis and validated using telmisartan. With some refinement and additional validation, our in vitro steatosis model system may be useful for profiling small molecule inhibitors and studying the mechanism of action of new drugs.

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Sjogren, Anna-Karin M., Maria Liljevald, Björn Glinghammar, Johanna Sagemark, Xue-Qing Li, Anna Jonebring, Ian Cotgreave, Gabriella Brolén, and Tommy B. Andersson. "Critical differences in toxicity mechanisms in induced pluripotent stem cell-derived hepatocytes, hepatic cell lines and primary hepatocytes." Archives of Toxicology 88, no. 7 (June 10, 2014): 1427–37. http://dx.doi.org/10.1007/s00204-014-1265-z.

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22

Hoff, V., LAP Faccioli, BD Paredes, KD Asensi, T. Bottaro, TH Kasai-Brunswick, TP Urmenyi, and RCS Goldenberg. "TRANSCRIPTOME ANALYSIS OF HEPATOCYTES DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS." Cytotherapy 23, no. 4 (April 2021): 36. http://dx.doi.org/10.1016/j.jcyt.2021.02.104.

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23

Sinton, Matthew C., Jose Meseguer-Ripolles, Baltasar Lucendo-Villarin, Amanda J. Drake, and David C. Hay. "Modeling human hepatic steatosis in pluripotent stem cell-derived hepatocytes." STAR Protocols 2, no. 2 (June 2021): 100493. http://dx.doi.org/10.1016/j.xpro.2021.100493.

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24

Szkolnicka, Dagmara, Wenli Zhou, Balta Lucendo-Villarin, and David C. Hay. "Pluripotent Stem Cell–Derived Hepatocytes: Potential and Challenges in Pharmacology." Annual Review of Pharmacology and Toxicology 53, no. 1 (January 6, 2013): 147–59. http://dx.doi.org/10.1146/annurev-pharmtox-011112-140306.

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25

Lucendo-Villarin, B., H. Rashidi, K. Cameron, and D. C. Hay. "Pluripotent stem cell derived hepatocytes: using materials to define cellular differentiation and tissue engineering." Journal of Materials Chemistry B 4, no. 20 (2016): 3433–42. http://dx.doi.org/10.1039/c6tb00331a.

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26

Wills, Lauren R., and Padmavathy Rajagopalan. "Advances in Human Induced Pluripotent Stem Cell-Derived Hepatocytes for Use in Toxicity Testing." Annals of Biomedical Engineering 48, no. 3 (August 1, 2019): 1045–57. http://dx.doi.org/10.1007/s10439-019-02331-z.

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Cayo, Max A., Jun Cai, Ann DeLaForest, Fallon K. Noto, Masato Nagaoka, Brian S. Clark, Ross F. Collery, Karim Si-Tayeb, and Stephen A. Duncan. "JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia." Hepatology 56, no. 6 (September 17, 2012): 2163–71. http://dx.doi.org/10.1002/hep.25871.

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Yang, Yang, Xiuhua Li, Wei Liu, Jingwen Chen, Changcheng Liu, Yongchao Cai, Yanxiang Song, Qinghe Tang, Chao Zhang, and Zhiying He. "Generation of Hepatocyte-Like Cells by Different Strategies for Liver Regeneration." Nano LIFE 08, no. 04 (November 30, 2018): 1841004. http://dx.doi.org/10.1142/s1793984418410040.

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Incidence and mortality of liver disease has increased globally in recent years. Orthotopic liver transplantation is a well-developed, effective therapy even for the end-stage liver diseases. However, the application of the technique is limited by the short supply of donors and the complexity of orthotopic liver transplantation. Therefore, hepatocyte transplantation as a new therapeutic option was developed. Unfortunately, the routine supply of high quality human hepatocytes was also restricted and the liver donor was lacking, too. Thus, exploration and study for available and renewable sources of nondonor hepatocytes are both necessary and important. Researches have proved that nondonor hepatocyte-like cells can be derived from various types of cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), liver stem cells (LSCs), fibroblasts by lineage reprogramming, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). In this review, we describe recent advances in the field of the cell therapy in liver regeneration. In addition, we also discuss the existing restrictions in these types of therapies and ongoing developments.

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29

Rambhatla, Lakshmi, Choy-Pik Chiu, Pratima Kundu, Yun Peng, and Melissa K. Carpenter. "Generation of Hepatocyte-Like Cells from Human Embryonic Stem Cells." Cell Transplantation 12, no. 1 (January 2003): 1–11. http://dx.doi.org/10.3727/000000003783985179.

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Use of human hepatocytes for therapeutic and drug discovery applications is hampered by limited tissue source and the inability of hepatocytes to proliferate and maintain function long term in vitro. Human embryonic stem (hES) cells are immortal and pluripotent and may provide a cell source for functional human hepatocytes. We report here that hES cells can be induced to differentiate into hepatocyte-like cells. Treatment with sodium butyrate induced hepatic differentiation as well as significant cell death, resulting in approximately 10–15% yield of a homogeneous population of cells. The differentiated cells have morphological features similar to that of primary hepatocytes and 70–80% of the cells express liver-associated proteins (albumin, alpha-1-antitrypsin, cytokeratin 8 and 18), accumulate glycogen, have inducible cytochrome P450 activity, and do not express alpha-fetoprotein. Because of the inherent proliferative capacity of hES cells, these cells may provide a reliable source of normal human hepatocytes for research and transplantation.

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Messina, Antonietta, Eléanor Luce, Nassima Benzoubir, Mattia Pasqua, Ulysse Pereira, Lydie Humbert, Thibaut Eguether, et al. "Evidence of Adult Features and Functions of Hepatocytes Differentiated from Human Induced Pluripotent Stem Cells and Self-Organized as Organoids." Cells 11, no. 3 (February 4, 2022): 537. http://dx.doi.org/10.3390/cells11030537.

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Background: Human-induced pluripotent stem cell-derived hepatocytes (iHeps) have been shown to have considerable potential in liver diseases, toxicity, and pharmacological studies. However, there is a growing need to obtain iHeps that are truly similar to primary adult hepatocytes in terms of morphological features and functions. We generated such human iHeps, self-assembled as organoids (iHep-Orgs). Methods: iPSC-derived hepatoblasts were self-assembled into spheroids and differentiated into mature hepatocytes modulating final step of differentiation. Results: In about four weeks of culture, the albumin secretion levels and the complete disappearance of α-fetoprotein from iHep-Orgs suggested the acquisition of a greater degree of maturation than those previously reported. The expression of apical transporters and bile acid secretion evidenced the acquisition of complex hepatocyte polarity as well as the development of a functional and well-defined bile canalicular network confirmed by computational analysis. Activities recorded for CYP450, UGT1A1, and alcohol dehydrogenase, response to hormonal stimulation, and glucose metabolism were also remarkable. Finally, iHep-Orgs displayed a considerable ability to detoxify pathological concentrations of lactate and ammonia. Conclusions: With features similar to those of primary adult hepatocytes, the iHep-Orgs thus produced could be considered as a valuable tool for the development and optimization of preclinical and clinical applications.

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Holmgren, Gustav, Benjamin Ulfenborg, Annika Asplund, Karin Toet, Christian X. Andersson, Ann Hammarstedt, Roeland Hanemaaijer, Barbara Küppers-Munther, and Jane Synnergren. "Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases." International Journal of Molecular Sciences 21, no. 2 (January 11, 2020): 469. http://dx.doi.org/10.3390/ijms21020469.

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There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor α (TNFα) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

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Alexanova, A., L. Viiri, R. Laaksonen, M. Kiamehr, and K. Aalto-Setälä. "Modeling Lipid Metabolism Of Coronary Artery Disease Patients With Induced Pluripotent Stem Cell Derived Hepatocytes." Atherosclerosis 287 (August 2019): e118-e119. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.344.

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Suzuki, Atsushi, Yun-wen Zheng, Shin Kaneko, Masafumi Onodera, Katashi Fukao, Hiromitsu Nakauchi, and Hideki Taniguchi. "Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver." Journal of Cell Biology 156, no. 1 (January 7, 2002): 173–84. http://dx.doi.org/10.1083/jcb.200108066.

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Using flow cytometry and single cell–based assays, we prospectively identified hepatic stem cells with multilineage differentiation potential and self-renewing capability. These cells could be clonally propagated in culture where they continuously produced hepatocytes and cholangiocytes as descendants while maintaining primitive stem cells. When cells that expanded in vitro were transplanted into recipient animals, they morphologically and functionally differentiated into hepatocytes and cholangiocytes with reconstitution of hepatocyte and bile duct structures. Furthermore, these cells differentiated into pancreatic ductal and acinar cells or intestinal epithelial cells when transplanted into pancreas or duodenal wall. These data indicate that self-renewing pluripotent stem cells persist in the developing mouse liver and that such cells can be induced to become cells of other organs of endodermal origin under appropriate microenvironment. Manipulation of hepatic stem cells may provide new insight into therapies for diseases of the digestive system.

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Horiuchi, Shinichiro, Yukie Kuroda, Yuji Komizu, and Seiichi Ishida. "Consideration of Commercially Available Hepatocytes as Cell Sources for Liver-Microphysiological Systems by Comparing Liver Characteristics." Pharmaceutics 15, no. 1 (December 24, 2022): 55. http://dx.doi.org/10.3390/pharmaceutics15010055.

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In recent years, microphysiological systems (MPS) have been developed to shorten the test period and reduce animal experiments for drug development. We examined cell sources for the liver-MPS, i.e., MPS mimicking liver function. For liver-MPS, liver-like cells with high liver functions are required. Cryo-preserved hepatocytes (cryoheps), the gold standard hepatocytes for in vitro drug development, present several disadvantages, including differences between lots due to individual donor variations or a limited cell supply from the same donor. As such, alternatives for cryoheps are sought. Hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-Heps), hepatocytes derived from liver-humanized mice (PXB-cells), and human liver cancer cells (HepG2 cells) were examined as source candidates for liver-MPS. Gene expression levels of the major cytochrome P450 of hiPSC-Heps, PXB cells, and HepG2 cells were compared with 22 lots of cryoheps, and the activities of hiPSC-Heps were compared with 8 lots of cryopreserved hepatocytes. A focused DNA microarray was used for the global gene analysis of the liver-like characteristics of hiPSC-Heps, PXB-cells, cryoheps, and HepG2 cells. Gene expression data from the focused microarray were analyzed by principal component analysis, hierarchical clustering, and enrichment analysis. The results indicated the characteristics of individual hepatocyte cell source and raised their consideration points as an alternative cell source candidate for liver-MPS. The study contributes to the repetitive utilization of a robust in vitro hepatic assay system over long periods with stable functionality.

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Ruangrung, Kanyarat, Warunya Chakritbudsabong, Sasitorn Rungarunlert, Duncan R. Smith, Suradej Hongeng, Naraporn Sirinonthanawech, Chompunuch Boonarkart, Rojjanaporn Pulmanausahakul, Ornpreya Suptawiwat, and Prasert Auewarakul. "Analysis of Tembusu virus infection of human cell lines and human induced pluripotent stem cell derived hepatocytes." Virus Research 292 (January 2021): 198252. http://dx.doi.org/10.1016/j.virusres.2020.198252.

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Du, Yingdong, Dawei Li, Conghui Han, Haoyu Wu, Longmei Xu, Ming Zhang, Jianjun Zhang, and Xiaosong Chen. "Exosomes from Human-Induced Pluripotent Stem Cell–Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway." Cellular Physiology and Biochemistry 43, no. 2 (2017): 611–25. http://dx.doi.org/10.1159/000480533.

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Background/Aims: This study aimed to evaluate the effects of exosomes produced by human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury, as well as the underlying mechanisms. Methods: Exosomes derived from hiPSC-MSCs were isolated and characterized both biochemically and biophysically. hiPSC-MSCs-Exo were injected systemically into a murine ischemia/reperfusion injury model via the inferior vena cava, and then the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Primary hepatocytes and human hepatocyte cell line HL7702 were used to test whether exosomes could induce hepatocytes proliferation in vitro. In addition, the expression levels of proliferation markers (proliferation cell nuclear antigen, PCNA; Phosphohistone-H3, PHH3) were measured by immunohistochemistry and Western blot. Moreover, SK inhibitor (SKI-II) and S1P1 receptor antagonist (VPC23019) were used to investigate the role of sphingosine kinase and sphingosine-1-phosphate-dependent pathway in the effects of hiPSC-MSCs-Exo on hepatocytes. Results: hiPSCs were efficiently induced into hiPSC-MSCs that had typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 100 to 200 nm and expressed exosome markers (Alix, CD63 and CD81). After hiPSC-MSCs-Exo administration, hepatocyte necrosis and sinusoidal congestion were markedly suppressed in the ischemia/reperfusion injury model, with lower histopathological scores. The levels of hepatocyte injury markers AST and ALT were significantly lower in the treatment group compared to control, and the expression levels of proliferation markers (PCNA and PHH3) were greatly induced after hiPSC-MSCs-Exo administration. Moreover, hiPSC-MSCs-Exo also induced primary hepatocytes and HL7702 cells proliferation in vitro in a dose-dependent manner. We found that hiPSC-MSCs-Exo could directly fuse with target hepatocytes or HL7702 cells and increase the activity of sphingosine kinase and synthesis of sphingosine-1-phosphate (S1P). Furthermore, the inhibition of SK1 or S1P1 receptor completely abolished the protective and proliferative effects of hiPSC-MSCs-Exo on hepatocytes, both in vitro and in vivo. Conclusions: Our results demonstrated that hiPSC-MSCs-Exo could alleviate hepatic I/R injury via activating sphingosine kinase and sphingosine-1-phosphate pathway in hepatocytes and promote cell proliferation. These findings represent a novel mechanism that potentially contributes to liver regeneration and have important implications for new therapeutic approaches to acute liver disease.

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Kojima, Hideaki, Hiroshi Yagi, Hiroko Kushige, Yukiko Toda, Kazuo Takayama, Shinako Masuda, Toshinori Morisaku, et al. "Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes." Cells 11, no. 8 (April 7, 2022): 1258. http://dx.doi.org/10.3390/cells11081258.

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Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research.

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Liu, Hua, Zhaohui Ye, Yonghak Kim, Saul Sharkis, and Yoon-Young Jang. "Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes." Hepatology 51, no. 5 (March 1, 2010): 1810–19. http://dx.doi.org/10.1002/hep.23626.

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Mittal, Nikhil, Farah Tasnim, Cao Yue, Yinghua Qu, Derek Phan, Yukti Choudhury, Min-Han Tan, and Hanry Yu. "Substrate Stiffness Modulates the Maturation of Human Pluripotent Stem-Cell-Derived Hepatocytes." ACS Biomaterials Science & Engineering 2, no. 9 (September 2016): 1649–57. http://dx.doi.org/10.1021/acsbiomaterials.6b00475.

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Kim, Jong Hyun, Min Wang, Jaehun Lee, Han-Jin Park, Chungseong Han, Hee Su Hong, Jeong Seong Kim, et al. "Prediction of hepatotoxicity for drugs using human pluripotent stem cell-derived hepatocytes." Cell Biology and Toxicology 34, no. 1 (April 5, 2017): 51–64. http://dx.doi.org/10.1007/s10565-017-9392-y.

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Holmgren, Gustav, Anna-Karin Sjögren, Isabel Barragan, Alan Sabirsh, Peter Sartipy, Jane Synnergren, Petter Björquist, Magnus Ingelman-Sundberg, Tommy B. Andersson, and Josefina Edsbagge. "Long-Term Chronic Toxicity Testing Using Human Pluripotent Stem Cell–Derived Hepatocytes." Drug Metabolism and Disposition 42, no. 9 (June 30, 2014): 1401–6. http://dx.doi.org/10.1124/dmd.114.059154.

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Iwamuro, Masaya, Hidenori Shiraha, Shuhei Nakaji, Masumi Furutani, Naoya Kobayashi, Akinobu Takaki, and Kazuhide Yamamoto. "A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes." BioMedical Engineering OnLine 11, no. 1 (2012): 93. http://dx.doi.org/10.1186/1475-925x-11-93.

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43

Grimm, Fabian Alexander, Yasuhiro Iwata, Oksana Sirenko, Michael Bittner, and Ivan Rusyn. "High-Content Assay Multiplexing for Toxicity Screening in Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Hepatocytes." ASSAY and Drug Development Technologies 13, no. 9 (November 2015): 529–46. http://dx.doi.org/10.1089/adt.2015.659.

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44

Chen, Yong, Yanfeng Li, Xia Wang, Wei Zhang, Vanessa Sauer, Chan-Jung Chang, Bing Han, et al. "Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes." Stem Cell Reports 5, no. 1 (July 2015): 22–30. http://dx.doi.org/10.1016/j.stemcr.2015.04.017.

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45

Kammerer, Sarah. "Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro." International Journal of Molecular Sciences 22, no. 19 (September 23, 2021): 10214. http://dx.doi.org/10.3390/ijms221910214.

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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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Gurevich, Igor, Sarah A. Burton, Christie Munn, Makiko Ohshima, Madelyn E. Goedland, Katherine Czysz, and Deepika Rajesh. "iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery." Biology Open 9, no. 12 (December 2, 2020): bio055087. http://dx.doi.org/10.1242/bio.055087.

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ABSTRACTNon-alcoholic fatty liver disease (NAFLD) affects 30–40% of adults and 10% of children in the US. About 20% of people with NAFLD develop non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis and liver cancer, and is projected to be a leading cause of liver transplantation in the near future. Human induced pluripotent stem cells (iPSC) from NASH patients are useful for generating a large number of hepatocytes for NASH modeling applications and identification of potential drug targets. We developed a novel defined in vitro differentiation process to generate cryopreservable hepatocytes using an iPSC panel of NASH donors and apparently healthy normal (AHN) controls. iPSC-derived hepatocytes displayed stage specific phenotypic markers, hepatocyte morphology, with bile canaliculi. Importantly, both fresh and cryopreserved definitive endoderm and hepatoblasts successfully differentiated to pure and functional hepatocytes with increased CYP3A4 activity in response to rifampicin and lipid accumulation upon fatty acid (FA) treatment. End-stage hepatocytes integrated into three-dimensional (3D) liver organoids and demonstrated increased levels of albumin secretion compared to aggregates consisting of hepatocytes alone. End-stage hepatocytes derived from NASH donors demonstrated spontaneous lipidosis without FA supplementation, recapitulating a feature of NASH hepatocytes in vivo. Cryopreserved hepatocytes generated by this protocol across multiple donors will provide a critical cell source to facilitate the fundamental understanding of NAFLD/NASH biology and potential high throughput screening applications for preclinical evaluation of therapeutic targets.

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Ghosheh, Nidal, Björn Olsson, Josefina Edsbagge, Barbara Küppers-Munther, Mariska Van Giezen, Annika Asplund, Tommy B. Andersson, et al. "Highly Synchronized Expression of Lineage-Specific Genes duringIn VitroHepatic Differentiation of Human Pluripotent Stem Cell Lines." Stem Cells International 2016 (2016): 1–22. http://dx.doi.org/10.1155/2016/8648356.

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Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, andCYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.

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Overeem, Arend W., Karin Klappe, Silvia Parisi, Petra Klöters-Planchy, Lavinija Mataković, Marines du Teil Espina, Christian A. Drouin, Karl Heinz Weiss, and Sven C. D. van IJzendoorn. "Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity." Journal of Hepatology 71, no. 2 (August 2019): 344–56. http://dx.doi.org/10.1016/j.jhep.2019.03.031.

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Kumar, A., D. Kumar, S. Shubham, S. Rooge, C. Bihari, M. M. Panicker, and S. K. Sarin. "P1128 : Hepatocytes differentiation from urine cells derived transgene free induced pluripotent stem cells." Journal of Hepatology 62 (April 2015): S774. http://dx.doi.org/10.1016/s0168-8278(15)31325-8.

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Jeong, J., S. B. Lee, K. Kang, H. Jeon, and D. Choi. "Induced Pluripotent Stem Cells (IPSCS) Derived Hepatocytes Function is Improved by Eliminating Transgene." Journal of Hepatology 64, no. 2 (2016): S201—S202. http://dx.doi.org/10.1016/s0168-8278(16)01713-x.

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