The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Lehmann, Vivian; Schene, Imre F.; Ardisasmita, Arif Ibrahim; Liv, Nalan; Veenendaal, Tineke; Klumperman, Judith; Doef, Hubert P.J. van der; Verkade, Henkjan J.; Verstegen, Monique M A; Laan, Luc J. W. van der; Jans, Judith; Verhoeven‐Duif, Nanda M.; Hasselt, Peter M. van; Nieuwenhuis, Edward E. S.; Spee, Bart; Fuchs, Sabine A.

doi:10.1002/jimd.12450

Cited by 5 publications

(5 citation statements)

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“… 36 COMMD1 -deficient dogs undergoing autologous intraportal transplantation of single cells derived from gene-corrected organoids survived up to 2 years. 37 Notably, intrahepatic cholangiocyte organoids (ICOs) have been developed with biopsy sample of 1 patient with ATP7B mutation, and ICOs displayed reduced cell viability after copper treatment 38 (Table 1 ).…”

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

“…Because of CFTR mutations, impaired forskolin-induced swelling occurred in these CF organoids, which indicated the malfunction of CFTR to transport chloride and corresponded to bile viscosity seen in CF patients. 38 , 40 , 41 CFTR correctors (VX-809 and VX-661) stabilize CFTR by filling into a hydrophobic pocket in the first transmembrane domain and linking together 4 helices that are thermodynamically unstable. 77 CFTR potentiator (VX-770) binds at the site involved in channel gating and stabilizes the open conformation of CFTR.…”

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

“… 79 , 80 As expected, impaired forskolin-induced swelling in human CF organoids was salvageable by a combination of CFTR correctors (VX-809 and VX-661) and CFTR potentiator (VX-770). 38 , 40 , 41 …”

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

“…ICOs have been generated from liver tissues from methylmalonic acidemia patients. 38 Propionylcarnitine was an intermediate product of branched-chain amino acid metabolism and was used as a clinical biomarker. Compared with controls, expanded ICO cells and culture media exhibited a significant increase in propionylcarnitine 38 (Table 1 ).…”

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

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Liver organoids: established tools for disease modeling and drug development

Sun

Kong

Zhao

et al. 2023

Hepatology Communications

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In the past decade, liver organoids have evolved rapidly as valuable research tools, providing novel insights into almost all types of liver diseases, including monogenic liver diseases, alcohol-associated liver disease, metabolic-associated fatty liver disease, various types of (viral) hepatitis, and liver cancers. Liver organoids in part mimic the microphysiology of the human liver and fill a gap in high-fidelity liver disease models to a certain extent. They hold great promise to elucidate the pathogenic mechanism of a diversity of liver diseases and play a crucial role in drug development. Moreover, it is challenging but opportunistic to apply liver organoids for tailored therapies of various liver diseases. The establishment, applications, and challenges of different types of liver organoids, for example, derived from embryonic, adult, or induced pluripotent stem cells, to model different liver diseases, are presented in this review.

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Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

Section: Liver Organoids In Modeling Monogenic And/or Neonatal Liver ...mentioning

confidence: 99%

See 2 more Smart Citations

Liver organoids: established tools for disease modeling and drug development

Sun

Kong

Zhao

et al. 2023

Hepatology Communications

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“…The characterization of the micro-scale morphology of the organoids both in expansion and differentiation media via transmission electron microscopy has been extensively investigated and reported previously. [456] HepG2 expansion medium: DMEM + GlutaMAX (Gibco, 31966, The Netherlands) supplemented with fetal bovine serum (FBS, 10% v/v, Gibco, 10270, The Netherlands) and penicillin/streptomycin (1%, Gibco, The Netherlands).…”

Section: Organoid Expansion and Differentiation Medium: Expansion Med...mentioning

confidence: 99%

Crafting Tissue Complexity

Núñez Bernal

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The global rise in life expectancy is accompanied by an increasing prevalence of chronic diseases, posing economic burdens and impacting patients' well-being. This surge in disease incidence challenges the drug discovery pipeline, calling for the adaptation of its rules and regulations to reduce the ever-increasing failure rates of new drugs. The staggering growth of the pharmaceutical industry in the last decades, and the high expenditure required to bring new drugs to the market is set to become an unsustainable issue in the coming years. Recently, far more attention has been focused on the preclinical phase of the pipeline, where drug evaluation culminates in animal testing, the current gold standard to ensure drug safety and efficacy before human trials. A consensus on the need for more complex and predictive human disease models has emerged and become a priority for scientists and policy makers in the past decade. Biofabrication, an emerging technology-driven field, has gained prominence in biomedical research for developing advanced in vitro models. Biofabrication is “the automated generation of biologically functional products with structural organization from living cells, bioactive molecules, biomaterials, cell aggregates such as micro-tissues, or hybrid cell-material constructs, through Bioprinting or Bioassembly and subsequent tissue maturation processes”. The last decades have seen the rapid development new bioprinting modalities, opening the door to the development of architecturally complex in vitro platforms where multi-cellular and multi-material structures can be more easily created. Considering the need for more complex preclinical models to bridge the translational gap between 2D in vitro models, animal testing and clinical trials, the overarching aim of this thesis was “to develop new biofabrication approaches, encompassing 3D bioprinting technologies, powerful biological building blocks, and smart biomaterials, that facilitate the development of advanced human in vitro models with native tissue-like functionality”. This research has introduced significant advancements within the field of biofabrication for the generation of human in vitro models. Through a comprehensive exploration that tackled challenges related to fundamental bioprinting principles, the biological intricacies, and the biochemical and material property requirements of bioprinted structures to better recapitulate native tissues, the developments described here have expanded the toolkit of biofabrication approaches. By introducing novel technologies, like the pioneering, layerless volumetric bioprinting strategy, and synergizing new and existing printing approaches to harness their unique advantages, this thesis showcases a variety of functional bioprinted tissue models that enable the study of biological processes in vitro. The thorough exploration of volumetric bioprinting, distinguished by its scalability, unparalleled design freedom, compatibility with advanced biological tools, and a growing library of smart materials, charts new paths toward the creation of clinically-relevant testing platforms. The bioprinted, tissue-specific in vitro models presented here offer enhanced physiological accuracy and predictability and hold the potential to incorporate patient-specific elements for personalized medicine. The toolkit developed in here represents a significant stride in bridging the translational gap of tissue-engineered in vitro models, particularly in the context of preclinical testing. All in all, the evolving landscape of biofabricated in vitro models holds promise for innovative approaches in the future.

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The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Lehmann

Schene

Ardisasmita

et al. 2021

J of Inher Metab Disea

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Inborn errors of metabolism (IEMs) comprise a diverse group of individually rare monogenic disorders that affect metabolic pathways. Mutations lead to enzymatic deficiency or dysfunction, which results in intermediate metabolite accumulation or deficit leading to disease phenotypes. Currently, treatment options for many IEMs are insufficient. Rarity of individual IEMs hampers therapy development and phenotypic and genetic heterogeneity suggest beneficial effects of personalized approaches. Recently, cultures of patient-own liverderived intrahepatic cholangiocyte organoids (ICOs) have been established. Since most metabolic genes are expressed in the liver, patient-derived ICOs represent exciting possibilities for in vitro modeling and personalized drug testing for IEMs. However, the exact application range of ICOs remains unclear.To address this, we examined which metabolic pathways can be studied with ICOs and what the potential and limitations of patient-derived ICOs are to model metabolic functions. We present functional assays in patient ICOs with defects in branched-chain amino acid metabolism (methylmalonic acidemia), Bart Spee and Sabine A. Fuchs authors contributed equally to this work. Sabine A. Fuchs: On behalf of United for Metabolic Diseases (UMD).

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The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Cited by 5 publications

References 60 publications

Liver organoids: established tools for disease modeling and drug development

Liver organoids: established tools for disease modeling and drug development

Crafting Tissue Complexity

The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

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