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Table 1 Major liver organized studies continued

From: Emerging liver organoid platforms and technologies

Studies Type of organoid Approach Unique features and applications
Huch et al. 2013, 2015 Biliary stem cell organoid - - Isolation and expansion of EPCAM+ biliary cells from liver biopsy
- 3D matrigel embedded culture
- Stable expansion of patient-specific adult liver biliary stem cells
- Bipotent biliary stem cells can generate functional hepatocytes and cholangiocytes in culture and form functional hepatocytes when engrafted in mice (low efficacy)
Takebe et al. 2013 Liver bud - Co-culture of iPSC-derived hepatic cells, HUVECs and MSCs
- Cells co-culture in 2D on matrigel forms 3D liver bud
- Self-organization of multiple cell types in vitro into a immature liver bud (lacks liver function)
- Liver bud develops into functional and vascularized liver tissue when engrafted into immuno-deficient mice
- Engrafted liver bud rescues genetic liver failure in mice
Ogawa et al. 2015 Cholangiocyte-like cell (CLC) organoids - Step wise differentiation of hiPSC through bipotent hepatoblast
- 3D matrigel embedded culture
- Cholangiocytes exhibit mature biliary markers and structures such as apical sodium-dependent bile acid transporter, secretin receptor, cilia and cystic fibrosis transmembrane conductance regulator (CFTR)
- In vitro modelling of cystic fibrosis with patient derived iPSC
Sampaziotis et al (2015, 2017) CLC organoids - Step wise differentiation of hiPSC through bipotent hepatoblast
- 3D matrigel embedded culture
- CLC is highly functional and utilized for validating polycystic drugs
- Organoids were used to model cystic fibrosis
- Engrafted CLC enable treatment of common bile duct (CBD) disorders
Broutier et al. 2017 Cancer organoids - Isolation of cancer cells from liver tumor tissue with modified media and protocol (Huch et al. 2015)
- 3D matrigel embedded culture
- Derivation of the cancer organoids (tumoroids) from major liver cancer subtypes including Hepatocellular Carcinoma (HCC), Intrahepatic Cholangiocarcinoma (ICC) and Hepato-Cholangiocarcinoma
- Tumoroids retain histological features of patient-derived tumor tissue after long term culture, preserve genetic alteration from original tumor and show metastatic potential
- Tumoroids were used for drug screening to identify potential patient specific therapy
Takebe et al. 2017 Liver bud - Co-culture of single donor iPSC-derived hepatic endoderm, endothelial and mesenchymal cells
- Engineered platform for large scale production
- Single donor iPSC-derived hepatic, endothelial and mesenchymal cells to generate patient specific liver buds
- Mechanized engineering platform for robust large scale production of liver bud
- Liver rescue experiments achieved in over 100 mice to demonstrate potential for regenerative therapy
Hu et al. 2018 Hepatocyte organoid - Isolation and expansion of hepatocytes from mouse liver and fetal human liver
- 3D Matrigel embedded culture
- Hepatocyte organoid exhibit high engraftment efficiency in mice
- The proliferating hepatocyte organoid resembles proliferating hepatocyte in liver with partial hepatectomy
- Hepatocyte organoid can be further matured in culture and exhibit major liver metabolic functions and forms bile canaliculi
Peng et al. 2018 Hepatocyte organoid - Expansion of isolated hepatocytes from mouse liver using pro-inflammatory cytokine TNFα
- 3D matrigel embedded culture
- Hepatocyte proliferation induced using inflammatory signals enriched in injured liver
- Hepatocyte organoids exhibit major liver functions and shows high engraftment capacity
Nie et al. 2018 Liver bud - Isolation of endothelial and mesenchymal cells from a single umbilical cord donor for liver bud organoid formation - Reduced liver bud size and maturation in vitro
- Differentiated liver bud consist mainly of hepatocytes and used for modeling HBV infection
Zhang et al. 2018;
Fu et al. 2019
Hepatocyte organoid - Expansion of isolated hepatocytes as a 2D proliferating hepatocyte progenitor
- Hepatocyte progenitor mature in 3D to form hepatocyte organoids
- Hepatocyte progenitor platform enabled large scale expansion of isolated primary adult human hepatocytes
- Hepatocyte progenitor mature into functional hepatocyte in vitro and in vivo. Cells demonstrate comparable engraftment efficiency compared to primary human hepatocytes
- Matured 3D hepatocyte organoids can be used for modelling HBV infection and reactivation in vitro
Vyas et al. 2018 Hepatobiliary organoid - Isolated human fetal liver progenitor cells (FLPC) are seeded and maintained in decellularized liver (ferret) disc - FLPC repopulated decellularized liver disc scaffold and differentiate to give rise to hepatobiliary organoid containing functionally mature AFP-ve hepatocytes and bile duct cells of different maturity
- Hepatobiliary organoid was used to investigate role of notch signaling in bile duct formation
Wu et al. 2019 Hepatobiliary organoid - Stepwise 2D differentiation of iPSC into hepatoblast and hepatobiliary cells
- Maintenance of a minimal mesenchymal population for hepatobiliary formation
- Cells differentiated in 2D culture generated a monolayer of hepatocytes with 3D biliary cysts
- Addition of cholesterol based reagent maintains hepatobiliary cells in culture and promotes maturity
- Transplanted organoids give rise to tissue containing both bile ducts and hepatocytes
Ouchi et al. 2019 Multi-cellular organoid - Stepwise differentiation of iPSC into liver organoid using an intermediate foregut spheroid progenitor
- 3D matrigel embedded culture
- Single cell analysis shows that organoid contains both parenchymal and non-parenchymal cell types of the liver
- Liver organoid treated with free fatty acid exhibit inflammatory response, undergo fibrogenesis which results in increase stiffness of organoids
Collin de l’Hortet et al. 2019 Multi-cellular organoid - Co-culture of iPSC derive hepatic cells with human microvascular endothelial cells, human mesenchymal cells, fibroblasts and macrophages in a decellularized rat liver scaffold - Large organoid measuring centimetres in size
- Modeling of Sirt1 depletion induced NASH under fatty acids enriched media
- NASH Model is capable of recapitulating steatosis, inflammation and ballooning phenotype
- Incorporation of media perfusion system enable NASH phenotype penetration in the core of large organoid.
Wang et al. 2019 Bipotent hepatic progenitor - Stepwise differentiation of PSC into bipotent hepatic progenitor organoids
- 3D matrigel embedded culture
- Highly expandable progenitor organoids that can generate hepatocytes or cholangiocytes in vitro and in vivo
- Co-culture of fetal-liver mesenchymal cells improves hepatocyte functions in organoid and enable modelling of alcohol-induced liver injury
Sun et al. 2019 Hepatocyte and Cancer organoid - SV40LT expressing fibroblast are transdifferentiated into hepatocytes (hiHeps) and cultured as 3D organoids in suspension
- Overexpression of HCC and ICC oncogenes to induce neoplastic transformation
- hiHep aggregates show polarity and exhibit better hepatocyte function than 2D cultured hiHep
- Introduction of Myc oncogene or ICC enriched mutations induces HCC and ICC transformation respectively. The transformed organoids form tumor in mice, that recapitulate features of patient derived tissue.
- Platform enables recapitulation of molecular and biogenesis events during neoplastic transformation
Artegiani et al. 2019 Biliary
Cancer organoid
- Cholangiocarcinoma associated genetic mutations are introduced into tissue derived biliary organoid to induce oncogenic transformation - Step-wise transformation of biliary organoids into cholangiocarcinoma organoids enable the investigation of tumor suppressor function of BAP1
- In vitro transformation platform enables investigation into cellular and molecular changes during neoplastic transformation
Mun et al. 2019; Akbari et al. 2019 Biliary stem cell organoid - Isolation and expansion of EPCAM+ bipotent progenitor from pluripotent stem cells
- 3D matrigel embedded culture
- Bipotent Progenitor derived from PSC is similar to the biliary stem cell organoid platform (Huch et al. 2015)
- Bipotent progenitor differentiates to hepatocytes in 3D, which exhibit liver functions and demonstrates regenerative and inflammatory responses.
- iPSC platform enable modeling of genetic disease with patient derived fibroblast
Koike et al. 2019 hepatic-biliary-pancreatic (HBP) endoderm organoid - Co-culture of PSC-derived midgut and foregut spheroids.
- Spheroid boundary further develops into HBP
- 3D matrigel embedded culture
- Spontaneous induction of hepatic-biliary-pancreatic domain formation and outgrowth to form bile duct linked hepatic and pancreatic tissues
- Validation of the role of HES1 in human liver and pancreas organogenesis.
Ramli et al. 2020 Hepatobiliary organoid - Stepwise differentiation of PSC in 2D and 3D culture
- 3D suspension culture
- Hepatobiliary organoid with a dense hepatocyte core and cystic cholangiocytes in the periphery
- Functional bile canaliculi network connecting both cell types observed in the organoid.
- Modelling of drug and disease induced cholestasis.
Shinozawa et al. 2020 Hepatocyte organoid - Stepwise differentiation of PSC in matrigel droplets
- Generation of an expandable foregut progenitor intermediate
- Spherical hepatocyte organoid containing a lumen that enable modelling of bile transportation
- High-throughput screening with organoids identified cholestasis inducing toxins