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Review
. 2022 Sep 9;12(1):152.
doi: 10.1186/s13578-022-00890-8.

"VSports注册入口" Liver organoids: an in vitro 3D model for liver cancer study

Renshun Dong  1   2   3 , Bixiang Zhang  4   5   6 , Xuewu Zhang  7   8   9
Affiliations
Review

"VSports在线直播" Liver organoids: an in vitro 3D model for liver cancer study

"V体育安卓版" Renshun Dong et al. Cell Biosci. .

Abstract

Primary liver cancer (PLC) is the second leading cause of cancer mortality worldwide, and its morbidity unceasingly increases these years. Hepatitis B virus (HBV) infection accounted for approximately 50% of hepatocellular carcinoma (HCC) cases globally in 2015 VSports手机版. Due to the lack of an effective model to study HBV-associated liver carcinogenesis, research has made slow progress. Organoid, an in vitro 3D model which maintains self-organization, has recently emerged as a powerful tool to investigate human diseases. In this review, we first summarize the categories and development of liver organoids. Then, we mainly focus on the functions of culture medium components and applications of organoids for HBV infection and HBV-associated liver cancer studies. Finally, we provide insights into a potential patient-derived organoid model from those infected with HBV based on our study, as well as the limitations and future applications of organoids in liver cancer research. .

Keywords: HBV infection; Liver organoid; Primary liver cancer V体育安卓版. .

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Conflict of interest statement

The authors declare that they have no competing interests.

"V体育官网" Figures

Fig. 1
Fig. 1
Features of liver organoids. As one kind of organoid models, liver organoids have the characteristic of long-term expansion and self-organization. In addition, liver organoids are of heterogeneity and with unique morphology features. Hep-Orgs are of pseudoglandular rosettes and Chol-Orgs are cryptomere
Fig. 2
Fig. 2
Liver organoids can be derived from various cells of origin. A Generation of liver organoids from healthy liver tissues. Liver organoids can be formed from hepatocytes, cholangiocytes and Lgr5+ liver stem cells. The isolated cells can be placed in Matrigel as extracellular matrix and seeded into culture vessels to generate organoids. Signaling pathways which are typically modulated to enable organoid formation are listed. B Generation of liver organoids from iPSCs. Liver organoids can be generated from iPSCs, usually by a three-stage differentiation process. Firstly, iPSCs can be derived to endoderm cells by exposure to Act A and Wnt. Then, these endoderm cells progress to a hepatic fate following induction of HGF and FGF signaling. These hepatic progenitors are hepatoblast-like cells and can form hepatocyte-like cells finally. C Generation of liver organoids from fibroblasts. Fibroblasts can be induced into hiHeps by exposure to FOXA3, HNF1A and HNF4A to activate trans-differentiation. Then, liver organoids can be generated from these hiHeps. D Generation of liver cancer organoids from liver cancer tissues. Similarly, liver cancer organoids can be formed from cancer cells isolated from cancer tissues. After seeding the isolated cells into culture vessels containing appropriate matrix, cancer organoids can be generated in the certain culture medium. Act A activin A, BMP bone morphogenetic protein, EGF epidermal growth factor, FGF fibroblast growth factor, HGF hepatocyte growth factor, iPSCs induced pluripotent stem cells, TGFbi transforming growth factor beta inhibitor, TNFa tumour necrosis factor-alpha
Fig. 3
Fig. 3
Applications of liver organoids. A Organoids derived from healthy liver tissues can be used as a model in basic research to investigate the cells of origin for liver cancer and the mechanism of carcinogenesis, especially in the HBV-associated liver cancers. B Organoids derived from liver cancer tissues can be expanded in vitro and cryopreserved enabling the establishment of biobanks. This is mainly used for drug screening in personalized medicine. Additionally, liver cancer organoids make it possible for the co-culture between cancer cells and other cells in microenvironment. Based on this technology, more basic research can be performed
Fig. 4
Fig. 4
HBV life cycle and the unpublished data of suppression of HBV expression in the PDO model. A HBV life cycle. HBV enters hepatocytes by membrane fusion and internalization through NTCP, followed by uncoating, and nuclear transport of the RC DNA. The RC DNA is converted to cccDNA, which serves as a template for the transcription of pregenomic HBV RNA and generates 4 different mRNA transcripts: 3.5 kb preC RNA and pgRNA, 2.4 and 2.1 kb preS/S mRNAs, and 0.7 kb HBx mRNA. These RNAs are exported to the cytoplasm, and plenty of HBV proteins are generated. pgRNA is selectively packaged inside core particles, followed by several progresses to generate RC DNA. Following viral assembly in the endoplasmic reticulum, mature HBV is released into the extracellular matrix. B Time course of relative HBsAg levels in expansion medium in the PDO model generated from patients infected with HBV. Error bars represent the mean ± SEM. C Heatmap of NTCP mRNA levels relative to GAPDH of different supplements added into basic medium with HEPES, B27, N2, Glutamax, N-acetyl-l-cysteine, EGF, FGF10 and HGF
Fig. 5
Fig. 5
Unknown features of patient-derived organoids from HBV+ patients. In basic research of HBV, whether there are other receptors except NTCP is still unknown. The differentiation level of HBV host cells also may influence the entering process of HBV. The role that other cells and cytokines in microenvironment play in the HBV life cycle requires more research. And whether the current culture system of PDOs is suitable for HBV replication or not remains unclear. More research is required to clarified the influence of additives in culture medium on HBV replication and the activity of HBV-associated signaling pathway. Before the culture of organoids, patients usually get anti-HBV therapies. The influence of these therapies remains unknown. The correlation between HBV copy number in serum and in culture medium requires more studies to clarify
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