Table 1 Major liver organized studies continued
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 |