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1. Metabolomic profiling of pheochromocytomas in dogs: Catecholamine phenotype and tricarboxylic acid cycle metabolites.

Author

van den Berg, Marit F., Bechmann, Nicole, Kooistra, Hans S., van Wolferen, Monique E., Timmermans‐Sprang, Elpetra P. M., Peitzsch, Mirko, and Galac, Sara

Subjects
LIQUID chromatography-mass spectrometry, KREBS cycle, SUCCINATE dehydrogenase, TRICARBOXYLIC acids, METABOLOMICS, LABORATORY dogs, GLUCOSE-6-phosphate dehydrogenase deficiency, PARAGANGLIOMA
Abstract

Background: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). Hypothesis/Objectives: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). Animals: Ten healthy dogs, 21 dogs with PCC. Methods: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. Results: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%‐98%] vs 14% [11%‐26%]; P <.001), and significantly lower tissue proportion of epinephrine (12% [1%‐62%] vs 86% [74%‐89%]; P <.001). Pheochromocytomas exhibited significantly lower fumarate (0.4‐fold; P <.001), and malate (0.5‐fold; P =.008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6‐fold; P =.015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25‐fold higher than in the other PCCs, suggesting an SDHx mutation. Conclusions and Clinical Importance: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Whole transcriptome analysis of canine pheochromocytoma and paraganglioma

Author

van den Berg, Marit F., primary, Kooistra, Hans S., additional, Grinwis, Guy C. M., additional, Nicoli, Stefano, additional, Golinelli, Stefania, additional, Stammeleer, Lisa, additional, van Wolferen, Monique E., additional, Timmermans-Sprang, Elpetra P. M., additional, Zandvliet, Maurice M. J. M., additional, van Steenbeek, Frank G., additional, and Galac, Sara, additional

Published
2023
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4. Prediction of outcome after ligation or thin film banding of extrahepatic shunts, based on plasma albumin concentration and hematologic expression of 8 target genes in 85 dogs

Author

Chirurgie, Sub GZ Herkauwer, CS_STEAM, Interne geneeskunde GD, Locomotion - Surgery (CA), STEAM, van Blokland-Post, Krista, Weber, Maarten F, van Wolferen, Monique E, Penning, Louis C, van Sluijs, Freek J, Kummeling, Anne, Chirurgie, Sub GZ Herkauwer, CS_STEAM, Interne geneeskunde GD, Locomotion - Surgery (CA), STEAM, van Blokland-Post, Krista, Weber, Maarten F, van Wolferen, Monique E, Penning, Louis C, van Sluijs, Freek J, and Kummeling, Anne

Published
2023

5. A human kidney and liver organoid‐based multi‐organ‐on‐a‐chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell‐derived extracellular vesicles

Author

Nguyen, Vivian V. T., primary, Ye, Shicheng, additional, Gkouzioti, Vasiliki, additional, van Wolferen, Monique E., additional, Yengej, Fjodor Yousef, additional, Melkert, Dennis, additional, Siti, Sofia, additional, de Jong, Bart, additional, Besseling, Paul J., additional, Spee, Bart, additional, van der Laan, Luc J. W., additional, Horland, Reyk, additional, Verhaar, Marianne C., additional, and van Balkom, Bas W. M., additional

Published
2022
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7. High level of polarized engraftment of porcine intrahepatic cholangiocyte organoids in decellularized liver scaffolds

Author

Krüger, Melanie, primary, Samsom, Roos‐Anne, additional, Oosterhoff, Loes A., additional, van Wolferen, Monique E., additional, Kooistra, Hans S., additional, Geijsen, Niels, additional, Penning, Louis C., additional, Kock, Linda M., additional, Sainz‐Arnal, Pilar, additional, Baptista, Pedro M., additional, and Spee, Bart, additional

Published
2022
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8. A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles

Author

Interne geneeskunde GD, CS_STEM, Nguyen, Vivian V T, Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E, Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J, Spee, Bart, van der Laan, Luc J W, Horland, Reyk, Verhaar, Marianne C, van Balkom, Bas W M, Interne geneeskunde GD, CS_STEM, Nguyen, Vivian V T, Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E, Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J, Spee, Bart, van der Laan, Luc J W, Horland, Reyk, Verhaar, Marianne C, and van Balkom, Bas W M

Published
2022

9. Volumetric Bioprinting of Organoids and Optically Tuned Hydrogels to Build Liver-Like Metabolic Biofactories

Author

Bernal, Paulina N., Bouwmeester, Manon C., Wolff, JM, Falandt, Marc, Florczak, Sammy, Rodriguez, Nuria Ginés, Li, Yang, Größbacher, Gabriel, Samsom, Roos-Anne, van Wolferen, Monique E., van der Laan, Luc, Delrot, Paul, Loterie, Damien, Malda, Jos, Moser, Christophe, Spee, Bart, Levato, Riccardo, Bernal, Paulina N., Bouwmeester, Manon C., Wolff, JM, Falandt, Marc, Florczak, Sammy, Rodriguez, Nuria Ginés, Li, Yang, Größbacher, Gabriel, Samsom, Roos-Anne, van Wolferen, Monique E., van der Laan, Luc, Delrot, Paul, Loterie, Damien, Malda, Jos, Moser, Christophe, Spee, Bart, and Levato, Riccardo

Abstract

Organ- and tissue-level biological functions are intimately linked to microscale cell–cell interactions and to the overarching tissue architecture. Together, biofabrication and organoid technologies offer the unique potential to engineer multi-scale living constructs, with cellular microenvironments formed by stem cell self-assembled structures embedded in customizable bioprinted geometries. This study introduces the volumetric bioprinting of complex organoid-laden constructs, which capture key functions of the human liver. Volumetric bioprinting via optical tomography shapes organoid-laden gelatin hydrogels into complex centimeter-scale 3D structures in under 20 s. Optically tuned bioresins enable refractive index matching of specific intracellular structures, countering the disruptive impact of cell-mediated light scattering on printing resolution. This layerless, nozzle-free technique poses no harmful mechanical stresses on organoids, resulting in superior viability and morphology preservation post-printing. Bioprinted organoids undergo hepatocytic differentiation showing albumin synthesis, liver-specific enzyme activity, and remarkably acquired native-like polarization. Organoids embedded within low stiffness gelatins (<2 kPa) are bioprinted into mathematically defined lattices with varying degrees of pore network tortuosity, and cultured under perfusion. These structures act as metabolic biofactories in which liver-specific ammonia detoxification can be enhanced by the architectural profile of the constructs. This technology opens up new possibilities for regenerative medicine and personalized drug testing.

Published
2022

10. High level of polarized engraftment of porcine intrahepatic cholangiocyte organoids in decellularized liver scaffolds

Author

Krüger, Melanie, Samsom, Roos Anne, Oosterhoff, Loes A., van Wolferen, Monique E., Kooistra, Hans S., Geijsen, Niels, Penning, Louis C., Kock, Linda M., Sainz-Arnal, Pilar, Baptista, Pedro M., Spee, Bart, Krüger, Melanie, Samsom, Roos Anne, Oosterhoff, Loes A., van Wolferen, Monique E., Kooistra, Hans S., Geijsen, Niels, Penning, Louis C., Kock, Linda M., Sainz-Arnal, Pilar, Baptista, Pedro M., and Spee, Bart

Abstract

In Europe alone, each year 5500 people require a life-saving liver transplantation, but 18% die before receiving one due to the shortage of donor organs. Whole organ engineering, utilizing decellularized liver scaffolds repopulated with autologous cells, is an attractive alternative to increase the pool of available organs for transplantation. The development of this technology is hampered by a lack of a suitable large-animal model representative of the human physiology and a reliable and continuous cell source. We have generated porcine intrahepatic cholangiocyte organoids from adult stem cells and demonstrate that these cultures remained stable over multiple passages whilst retaining the ability to differentiate into hepatocyte- and cholangiocyte-like cells. Recellularization onto porcine scaffolds was efficient and the organoids homogeneously differentiated, even showing polarization. Our porcine intrahepatic cholangiocyte system, combined with porcine liver scaffold paves the way for developing whole liver engineering in a relevant large-animal model.

Published
2022

11. A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles

Author

Nguyen, Vivian V T, Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E, Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J, Spee, Bart, van der Laan, Luc J W, Horland, Reyk, Verhaar, Marianne C, van Balkom, Bas W M, Nguyen, Vivian V T, Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E, Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J, Spee, Bart, van der Laan, Luc J W, Horland, Reyk, Verhaar, Marianne C, and van Balkom, Bas W M

Abstract

Mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) show therapeutic potential in multiple disease models, including kidney injury. Clinical translation of sEVs requires further preclinical and regulatory developments, including elucidation of the biodistribution and mode of action (MoA). Biodistribution can be determined using labelled sEVs in animal models which come with ethical concerns, are time-consuming and expensive, and may not well represent human physiology. We hypothesised that, based on developments in microfluidics and human organoid technology, in vitro multi-organ-on-a-chip (MOC) models allow us to study effects of sEVs in modelled human organs like kidney and liver in a semi-systemic manner. Human kidney- and liver organoids combined by microfluidic channels maintained physiological functions, and a kidney injury model was established using hydrogenperoxide. MSC-sEVs were isolated, and their size, density and potential contamination were analysed. These sEVs stimulated recovery of the renal epithelium after injury. Microscopic analysis shows increased accumulation of PKH67-labelled sEVs not only in injured kidney cells, but also in the unharmed liver organoids, compared to healthy control conditions. In conclusion, this new MOC model recapitulates therapeutic efficacy and biodistribution of MSC-sEVs as observed in animal models. Its human background allows for in-depth analysis of the MoA and identification of potential side effects.

Published
2022

12. A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles

Author

MS Nefrologie, Nefro Vasculaire Geneeskunde, UMC Utrecht Holding, Circulatory Health, Regenerative Medicine and Stem Cells, Nguyen, Vivian V.T., Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E., Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J., Spee, Bart, van der Laan, Luc J.W., Horland, Reyk, Verhaar, Marianne C., van Balkom, Bas W.M., MS Nefrologie, Nefro Vasculaire Geneeskunde, UMC Utrecht Holding, Circulatory Health, Regenerative Medicine and Stem Cells, Nguyen, Vivian V.T., Ye, Shicheng, Gkouzioti, Vasiliki, van Wolferen, Monique E., Yengej, Fjodor Yousef, Melkert, Dennis, Siti, Sofia, de Jong, Bart, Besseling, Paul J., Spee, Bart, van der Laan, Luc J.W., Horland, Reyk, Verhaar, Marianne C., and van Balkom, Bas W.M.

Published
2022

13. Bioprinting of Human Liver‐Derived Epithelial Organoids for Toxicity Studies

Author

Bouwmeester, Manon C., primary, Bernal, Paulina N., additional, Oosterhoff, Loes A., additional, van Wolferen, Monique E., additional, Lehmann, Vivian, additional, Vermaas, Monique, additional, Buchholz, Maj‐Britt, additional, Peiffer, Quentin C., additional, Malda, Jos, additional, van der Laan, Luc J. W., additional, Kramer, Nynke I., additional, Schneeberger, Kerstin, additional, Levato, Riccardo, additional, and Spee, Bart, additional

Published
2021
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14. Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis

Author

Valtolina, Chiara, Robben, Joris H., van Wolferen, Monique E., Kruitwagen, Hedwig S., Corbee, Ronald J., Favier, Robert P., Penning, Louis C., dCSCA AVR, Intensieve Zorgafdeling, dCSCA RMSC-1, Biochemisch laboratorium, LS Interne geneeskunde, LS Algemene chirurgie, Sub Hepatologie, Onderzoek, CS_Welfare & emerging diseases, CS_STEM, dCSCA AVR, Intensieve Zorgafdeling, dCSCA RMSC-1, Biochemisch laboratorium, LS Interne geneeskunde, LS Algemene chirurgie, Sub Hepatologie, Onderzoek, CS_Welfare & emerging diseases, and CS_STEM

Subjects
Feline hepatic lipidosis, medicine.medical_specialty, SREBP-1c, 040301 veterinary sciences, Gene Expression, Biology, Cat Diseases, Lipidoses, 0403 veterinary science, 03 medical and health sciences, Internal medicine, Hepatic lipogenesis, medicine, Animals, PPAR alpha, Small Animals, Gene, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, CATS, Lipogenesis, Fatty acid, qRT-PCR, Original Articles, 04 agricultural and veterinary sciences, medicine.disease, Lipids, PPAR gamma, de novo lipogenesis, Real-time polymerase chain reaction, Endocrinology, Liver, chemistry, Hepatic lipid, Cats, Fatty Acid Synthases, Sterol Regulatory Element Binding Protein 1
Abstract

Objectives The aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL). Methods Lipogenic gene expression of peroxisome proliferator-activated receptor-alpha ( PPAR-α), peroxisome proliferator-activated receptor-gamma ( PPAR-γ), fatty acid synthase ( FASN) and sterol regulatory element-binding factor ( SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats. Results In liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different ( P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group ( P = 0.039). Conclusions and relevance The downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL.

Published
2019

15. Association of circulating microRNA‐122 and microRNA‐29a with stage of fibrosis and progression of chronic hepatitis in Labrador Retrievers

Author

Sakai, Manabu, Spee, Bart, Grinwis, Guy C M, Penning, Louis C, van Wolferen, Monique E, van der Laan, Luc J W, Fieten, Hille, dCSCA RMSC-1, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, LS Pathologie, PB AVM, Dep Pathobiologie, Applied Veterinary Research, dCSCA AVR, dCSCA RMSC-1, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, LS Pathologie, PB AVM, Dep Pathobiologie, Applied Veterinary Research, dCSCA AVR, and Surgery

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, 040301 veterinary sciences, canine, Standard Article, 030204 cardiovascular system & hematology, Real-Time Polymerase Chain Reaction, Gastroenterology, 0403 veterinary science, 03 medical and health sciences, 0302 clinical medicine, Dogs, Chronic hepatitis, SDG 3 - Good Health and Well-being, Fibrosis, Internal medicine, medicine, Animals, Dog Diseases, Stage (cooking), Hepatitis, Chronic, Retrospective Studies, Hepatitis, Liver injury, lcsh:Veterinary medicine, General Veterinary, Hepatology, business.industry, cirrhosis, fibrosis, Retrospective cohort study, 04 agricultural and veterinary sciences, medicine.disease, Standard Articles, Circulating MicroRNA, MicroRNAs, Case-Control Studies, dog, Disease Progression, lcsh:SF600-1100, Female, SMALL ANIMAL, business, Biomarkers, liver injury
Abstract

BACKGROUND: Chronic hepatitis (CH) in dogs is common and has the tendency to progress to liver cirrhosis (LC). Circulating microRNAs might have the potential as markers for disease progression. OBJECTIVES: To investigate whether concentration of specific microRNAs in serum correlate with the stage and grade of CH in Labrador Retrievers. ANIMALS: Twenty-two Labrador Retrievers with histological CH (n = 8), LC (n = 7), and normal liver (NL, n = 7). METHODS: In this retrospective study, serum concentrations of miR-122, miR-29a, miR-133a, miR-181b, and miR-17-5p were measured by quantitative real-time PCR and evaluated using univariate linear regression in dogs. A multivariate model was fit including the grade of hepatitis and the stage of fibrosis. RESULTS: Of the 5 microRNAs, only circulating miR-122 and miR-29a were significantly associated with the grade of hepatitis and the stage of fibrosis. A positive correlation was identified between the grade of hepatitis with miR-122 (rs = 0.79, P

Published
2018

16. Bioprinting of Human Liver-Derived Epithelial Organoids for Toxicity Studies

Author

Bouwmeester, Manon C., Bernal, Paulina N., Oosterhoff, Loes A., van Wolferen, Monique E., Lehmann, Vivian, Vermaas, Monique, Buchholz, Maj Britt, Peiffer, Quentin C., Malda, Jos, van der Laan, Luc J.W., Kramer, Nynke I., Schneeberger, Kerstin, Levato, Riccardo, Spee, Bart, Bouwmeester, Manon C., Bernal, Paulina N., Oosterhoff, Loes A., van Wolferen, Monique E., Lehmann, Vivian, Vermaas, Monique, Buchholz, Maj Britt, Peiffer, Quentin C., Malda, Jos, van der Laan, Luc J.W., Kramer, Nynke I., Schneeberger, Kerstin, Levato, Riccardo, and Spee, Bart

Abstract

There is a need for long-lived hepatic in vitro models to better predict drug induced liver injury (DILI). Human liver-derived epithelial organoids are a promising cell source for advanced in vitro models. Here, organoid technology is combined with biofabrication techniques, which holds great potential for the design of in vitro models with complex and customizable architectures. Here, porous constructs with human hepatocyte-like cells derived from organoids are generated using extrusion-based printing technology. Cell viability of bioprinted organoids remains stable for up to ten days (88–107% cell viability compared to the day of printing). The expression of hepatic markers, transporters, and phase I enzymes increased compared to undifferentiated controls, and is comparable to non-printed controls. Exposure to acetaminophen, a well-known hepatotoxic compound, decreases cell viability of bioprinted liver organoids to 21–51% (p < 0.05) compared to the start of exposure, and elevated levels of damage marker miR-122 are observed in the culture medium, indicating the potential use of the bioprinted constructs for toxicity testing. In conclusion, human liver-derived epithelial organoids can be combined with a biofabrication approach, thereby paving the way to create perfusable, complex constructs which can be used as toxicology- and disease-models.

Published
2021

17. Bioprinting of Human Liver-Derived Epithelial Organoids for Toxicity Studies

Author

Orthopaedie Onderzoek, Metabole ziekten onderzoek 2, Regenerative Medicine and Stem Cells, MDL onderzoek 2, Other research (not in main researchprogram), Bouwmeester, Manon C., Bernal, Paulina N., Oosterhoff, Loes A., van Wolferen, Monique E., Lehmann, Vivian, Vermaas, Monique, Buchholz, Maj Britt, Peiffer, Quentin C., Malda, Jos, van der Laan, Luc J.W., Kramer, Nynke I., Schneeberger, Kerstin, Levato, Riccardo, Spee, Bart, Orthopaedie Onderzoek, Metabole ziekten onderzoek 2, Regenerative Medicine and Stem Cells, MDL onderzoek 2, Other research (not in main researchprogram), Bouwmeester, Manon C., Bernal, Paulina N., Oosterhoff, Loes A., van Wolferen, Monique E., Lehmann, Vivian, Vermaas, Monique, Buchholz, Maj Britt, Peiffer, Quentin C., Malda, Jos, van der Laan, Luc J.W., Kramer, Nynke I., Schneeberger, Kerstin, Levato, Riccardo, and Spee, Bart

Published
2021

18. Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Author

Krüger, Melanie, Oosterhoff, Loes A, van Wolferen, Monique E, Schiele, Simon A, Walther, Andreas, Geijsen, Niels, De Laporte, Laura, van der Laan, Luc J W, Kock, Linda M, Spee, Bart, Interne geneeskunde GD, dCSCA RMSC-1, CS_STEM, Orthopaedic Biomechanics, Interne geneeskunde GD, dCSCA RMSC-1, CS_STEM, and Surgery

Subjects
Adult, Scaffold, Hydrogels/pharmacology, Cellular differentiation, Cell, Biomedical Engineering, Pharmaceutical Science, 02 engineering and technology, 010402 general chemistry, cellulose nanofibril hydrogels, 01 natural sciences, Biomaterials, Mice, Matrigel, Tissue engineering, medicine, Organoid, Humans, Animals, clinical‐grade scaffolds, Cellulose, liver organoid scaffolds, Basement membrane, clinical-grade scaffolds, liver organoids, engineered tissues, Chemistry, Hydrogels, Cell Differentiation, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Cell biology, Transplantation, Organoids, medicine.anatomical_structure, Liver, 0210 nano-technology
Abstract

To replicate functional liver tissue in vitro for drug testing or transplantation, 3D tissue engineering requires representative cell models as well as scaffolds that not only promote tissue production but also are applicable in a clinical setting. Recently, adult liver-derived liver organoids are found to be of much interest due to their genetic stability, expansion potential, and ability to differentiate toward a hepatocyte-like fate. The current standard for culturing these organoids is a basement membrane hydrogel like Matrigel (MG), which is derived from murine tumor material and apart from its variability and high costs, possesses an undefined composition and is therefore not clinically applicable. Here, a cellulose nanofibril (CNF) hydrogel is investigated with regard to its potential to serve as an alternative clinical grade scaffold to differentiate liver organoids. The results show that its mechanical properties are suitable for differentiation with overall, either equal or improved, functionality of the hepatocyte-like cells compared to MG. Therefore, and because of its defined and tunable chemical definition, the CNF hydrogel presents a viable alternative to MG for liver tissue engineering with the option for clinical use.

Published
2020

19. Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

Author

Haaker, Maya W, Kruitwagen, Hedwig S, Vaandrager, Arie B, Houweling, Martin, Penning, Louis C, Molenaar, Martijn R, van Wolferen, Monique E, Oosterhoff, Loes A, Spee, Bart, Helms, J Bernd, Haaker, Maya W, Kruitwagen, Hedwig S, Vaandrager, Arie B, Houweling, Martin, Penning, Louis C, Molenaar, Martijn R, van Wolferen, Monique E, Oosterhoff, Loes A, Spee, Bart, and Helms, J Bernd

Published
2020

20. Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Author

Interne geneeskunde GD, dCSCA RMSC-1, Krüger, Melanie, Oosterhoff, Loes A, van Wolferen, Monique E, Schiele, Simon A, Walther, Andreas, Geijsen, Niels, De Laporte, Laura, van der Laan, Luc J W, Kock, Linda M, Spee, Bart, Interne geneeskunde GD, dCSCA RMSC-1, Krüger, Melanie, Oosterhoff, Loes A, van Wolferen, Monique E, Schiele, Simon A, Walther, Andreas, Geijsen, Niels, De Laporte, Laura, van der Laan, Luc J W, Kock, Linda M, and Spee, Bart

Published
2020

21. Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease

Author

Interne geneeskunde GD, dCSCA RMSC-1, Onderzoek, Chirurgie, dCSCA AVR, LS Interne geneeskunde, Operatiekamer en sterilisatie, Diagnostische beeldvorming, VPDC pathologie, dPB CR, Faculteit Diergeneeskunde, CS_Genetics, Kruitwagen, Hedwig S, Oosterhoff, Loes A, van Wolferen, Monique E, Chen, Chen, Nantasanti Assawarachan, Sathidpak, Schneeberger, Kerstin, Kummeling, Anne, van Straten, Giora, Akkerdaas, Ies C, Vinke, Christel R, van Steenbeek, Frank G, van Bruggen, Leonie W L, Wolfswinkel, Jeannette, Grinwis, Guy C M, Fuchs, Sabine A, Gehart, Helmuth, Geijsen, Niels, Vries, Robert G, Clevers, Hans, Rothuizen, Jan, Schotanus, Baukje A, Penning, Louis C, Spee, Bart, Interne geneeskunde GD, dCSCA RMSC-1, Onderzoek, Chirurgie, dCSCA AVR, LS Interne geneeskunde, Operatiekamer en sterilisatie, Diagnostische beeldvorming, VPDC pathologie, dPB CR, Faculteit Diergeneeskunde, CS_Genetics, Kruitwagen, Hedwig S, Oosterhoff, Loes A, van Wolferen, Monique E, Chen, Chen, Nantasanti Assawarachan, Sathidpak, Schneeberger, Kerstin, Kummeling, Anne, van Straten, Giora, Akkerdaas, Ies C, Vinke, Christel R, van Steenbeek, Frank G, van Bruggen, Leonie W L, Wolfswinkel, Jeannette, Grinwis, Guy C M, Fuchs, Sabine A, Gehart, Helmuth, Geijsen, Niels, Vries, Robert G, Clevers, Hans, Rothuizen, Jan, Schotanus, Baukje A, Penning, Louis C, and Spee, Bart

Published
2020

22. Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease

Author

Kruitwagen, Hedwig S, Oosterhoff, Loes A, van Wolferen, Monique E, Chen, Chen, Nantasanti Assawarachan, Sathidpak, Schneeberger, Kerstin, Kummeling, Anne, van Straten, Giora, Akkerdaas, Ies C, Vinke, Christel R, van Steenbeek, Frank G, van Bruggen, Leonie W L, Wolfswinkel, Jeannette, Grinwis, Guy C M, Fuchs, Sabine A, Gehart, Helmuth, Geijsen, Niels, Vries, Robert G, Clevers, Hans, Rothuizen, Jan, Schotanus, Baukje A, Penning, Louis C, Spee, Bart, Kruitwagen, Hedwig S, Oosterhoff, Loes A, van Wolferen, Monique E, Chen, Chen, Nantasanti Assawarachan, Sathidpak, Schneeberger, Kerstin, Kummeling, Anne, van Straten, Giora, Akkerdaas, Ies C, Vinke, Christel R, van Steenbeek, Frank G, van Bruggen, Leonie W L, Wolfswinkel, Jeannette, Grinwis, Guy C M, Fuchs, Sabine A, Gehart, Helmuth, Geijsen, Niels, Vries, Robert G, Clevers, Hans, Rothuizen, Jan, Schotanus, Baukje A, Penning, Louis C, and Spee, Bart

Abstract

The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson's disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease.

Published
2020

23. Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis

Author

dCSCA AVR, Intensieve Zorgafdeling, dCSCA RMSC-1, Biochemisch laboratorium, LS Interne geneeskunde, LS Algemene chirurgie, Sub Hepatologie, Onderzoek, CS_Welfare & emerging diseases, Valtolina, Chiara, Robben, Joris H., van Wolferen, Monique E., Kruitwagen, Hedwig S., Corbee, Ronald J., Favier, Robert P., Penning, Louis C., dCSCA AVR, Intensieve Zorgafdeling, dCSCA RMSC-1, Biochemisch laboratorium, LS Interne geneeskunde, LS Algemene chirurgie, Sub Hepatologie, Onderzoek, CS_Welfare & emerging diseases, Valtolina, Chiara, Robben, Joris H., van Wolferen, Monique E., Kruitwagen, Hedwig S., Corbee, Ronald J., Favier, Robert P., and Penning, Louis C.

Published
2020

24. Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

Author

LS Veterinaire biochemie, dB&C FR-RMSC RMSC, LS Interne geneeskunde, dCSCA RMSC-1, Onderzoek, dCSCA AVR, Sub Biochemie Algemeen, Biochemisch laboratorium, Dep Biochemie en Celbiologie, dB&C FR-RMSC FR, Haaker, Maya W, Kruitwagen, Hedwig S, Vaandrager, Arie B, Houweling, Martin, Penning, Louis C, Molenaar, Martijn R, van Wolferen, Monique E, Oosterhoff, Loes A, Spee, Bart, Helms, J Bernd, LS Veterinaire biochemie, dB&C FR-RMSC RMSC, LS Interne geneeskunde, dCSCA RMSC-1, Onderzoek, dCSCA AVR, Sub Biochemie Algemeen, Biochemisch laboratorium, Dep Biochemie en Celbiologie, dB&C FR-RMSC FR, Haaker, Maya W, Kruitwagen, Hedwig S, Vaandrager, Arie B, Houweling, Martin, Penning, Louis C, Molenaar, Martijn R, van Wolferen, Monique E, Oosterhoff, Loes A, Spee, Bart, and Helms, J Bernd

Published
2020

25. A Chemically Defined Hydrogel for Human Liver Organoid Culture

Author

Afd Pharmaceutics, Interne geneeskunde GD, dCSCA AVR, dCSCA RMSC-1, Pharmaceutics, CS_STEM, CS_Genetics, Ye, Shicheng, Boeter, Jochem W.B., Mihajlovic, Marko, van Steenbeek, Frank G., van Wolferen, Monique E., Oosterhoff, Loes A., Marsee, Ary, Caiazzo, Massimiliano, van der Laan, Luc J.W., Penning, Louis C., Vermonden, Tina, Spee, Bart, Schneeberger, Kerstin, Afd Pharmaceutics, Interne geneeskunde GD, dCSCA AVR, dCSCA RMSC-1, Pharmaceutics, CS_STEM, CS_Genetics, Ye, Shicheng, Boeter, Jochem W.B., Mihajlovic, Marko, van Steenbeek, Frank G., van Wolferen, Monique E., Oosterhoff, Loes A., Marsee, Ary, Caiazzo, Massimiliano, van der Laan, Luc J.W., Penning, Louis C., Vermonden, Tina, Spee, Bart, and Schneeberger, Kerstin

Published
2020

26. Large-scale Production of LGR5-positive Bipotential Human Liver Stem Cells.

Author

Onderzoek, dCSCA RMSC-1, Sub General Pharmacology, dCSCA AVR, Biochemisch laboratorium, Faculteit Diergeneeskunde, Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, Spee, Bart, Onderzoek, dCSCA RMSC-1, Sub General Pharmacology, dCSCA AVR, Biochemisch laboratorium, Faculteit Diergeneeskunde, Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, and Spee, Bart

Published
2020

27. Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Author

Hubrecht Institute with UMC, Krüger, Melanie, Oosterhoff, Loes A, van Wolferen, Monique E, Schiele, Simon A, Walther, Andreas, Geijsen, Niels, De Laporte, Laura, van der Laan, Luc J W, Kock, Linda M, Spee, Bart, Hubrecht Institute with UMC, Krüger, Melanie, Oosterhoff, Loes A, van Wolferen, Monique E, Schiele, Simon A, Walther, Andreas, Geijsen, Niels, De Laporte, Laura, van der Laan, Luc J W, Kock, Linda M, and Spee, Bart

Published
2020

28. Large-scale Production of LGR5-positive Bipotential Human Liver Stem Cells

Author

MDL onderzoek 2, Onderzoek Precision medicine, Metabole ziekten onderzoek 1, Metabole ziekten patientenzorg, Regenerative Medicine and Stem Cells, Child Health, CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, Spee, Bart, MDL onderzoek 2, Onderzoek Precision medicine, Metabole ziekten onderzoek 1, Metabole ziekten patientenzorg, Regenerative Medicine and Stem Cells, Child Health, CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, and Spee, Bart

Published
2020

30. A Chemically Defined Hydrogel for Human Liver Organoid Culture

Author

Ye, Shicheng, primary, Boeter, Jochem W.B., additional, Mihajlovic, Marko, additional, van Steenbeek, Frank G., additional, van Wolferen, Monique E., additional, Oosterhoff, Loes A., additional, Marsee, Ary, additional, Caiazzo, Massimiliano, additional, van der Laan, Luc J.W., additional, Penning, Louis C., additional, Vermonden, Tina, additional, Spee, Bart, additional, and Schneeberger, Kerstin, additional

Published
2020
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31. Large‐Scale Production of LGR5‐Positive Bipotential Human Liver Stem Cells

Author

Schneeberger, Kerstin, primary, Sánchez‐Romero, Natalia, additional, Ye, Shicheng, additional, van Steenbeek, Frank G., additional, Oosterhoff, Loes A., additional, Pla Palacin, Iris, additional, Chen, Chen, additional, van Wolferen, Monique E., additional, van Tienderen, Gilles, additional, Lieshout, Ruby, additional, Colemonts‐Vroninks, Haaike, additional, Schene, Imre, additional, Hoekstra, Ruurdtje, additional, Verstegen, Monique M.A., additional, van der Laan, Luc J.W., additional, Penning, Louis C., additional, Fuchs, Sabine A., additional, Clevers, Hans, additional, De Kock, Joery, additional, Baptista, Pedro M., additional, and Spee, Bart, additional

Published
2020
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32. Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease

Author

Kruitwagen, Hedwig S., primary, Oosterhoff, Loes A., additional, van Wolferen, Monique E., additional, Chen, Chen, additional, Nantasanti Assawarachan, Sathidpak, additional, Schneeberger, Kerstin, additional, Kummeling, Anne, additional, van Straten, Giora, additional, Akkerdaas, Ies C., additional, Vinke, Christel R., additional, van Steenbeek, Frank G., additional, van Bruggen, Leonie W.L., additional, Wolfswinkel, Jeannette, additional, Grinwis, Guy C.M., additional, Fuchs, Sabine A., additional, Gehart, Helmuth, additional, Geijsen, Niels, additional, Vries, Robert G., additional, Clevers, Hans, additional, Rothuizen, Jan, additional, Schotanus, Baukje A., additional, Penning, Louis C., additional, and Spee, Bart, additional

Published
2020
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33. Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Author

Kruitwagen, Hedwig S., Oosterhoff, Loes A., Vernooij, Ingrid G W H, Schrall, Ingrid M., van Wolferen, Monique E., Bannink, Farah, Roesch, Camille, van Uden, Lisa, Molenaar, Martijn R., Helms, J. Bernd, Grinwis, Guy C.M., Verstegen, Monique M A, van der Laan, Luc J W, Huch, Meritxell, Geijsen, Niels, Vries, Robert R G, Clevers, Hans, Rothuizen, Jan, Schotanus, Baukje A., Penning, Louis C., Spee, Bart, dB&C FR-RMSC FR, dCSCA RMSC-1, dPB CR, dCSCA AVR, Onderzoek, Biochemisch laboratorium, LS Pathologie, Sub Biochemie Algemeen, Dep Biochemie en Celbiologie, LS Veterinaire biochemie, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, Applied Veterinary Research, Dep Pathobiologie, Faculteit Diergeneeskunde, LS Interne geneeskunde, Surgery, Hubrecht Institute for Developmental Biology and Stem Cell Research, dB&C FR-RMSC FR, dCSCA RMSC-1, dPB CR, dCSCA AVR, Onderzoek, Biochemisch laboratorium, LS Pathologie, Sub Biochemie Algemeen, Dep Biochemie en Celbiologie, LS Veterinaire biochemie, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, Applied Veterinary Research, Dep Pathobiologie, Faculteit Diergeneeskunde, LS Interne geneeskunde, Huch Ortega, Meritxell [0000-0002-1545-5265], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Pathology, species differences, Biochemistry, Liver disease, 0302 clinical medicine, Lipid droplet, disease modeling, Non-U.S. Gov't, lcsh:QH301-705.5, lcsh:R5-920, Research Support, Non-U.S. Gov't, hepatic steatosis, Fatty liver, Cell Differentiation, 3. Good health, Organoids, Adult Stem Cells, Liver, 030220 oncology & carcinogenesis, Female, Stem cell, lcsh:Medicine (General), Adult stem cell, Feline hepatic lipidosis, medicine.medical_specialty, feline liver organoids, Biology, Research Support, 03 medical and health sciences, Organ Culture Techniques, Report, Internal medicine, Genetics, medicine, Organoid, Journal Article, Animals, Animal, Cell Biology, medicine.disease, Fatty Liver, Disease Models, Animal, adult liver stem cells, 030104 developmental biology, Endocrinology, lcsh:Biology (General), Disease Models, Cats, Hepatocytes, feline hepatic lipidosis, Steatosis, Developmental Biology
Abstract

Summary Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research., Highlights • Feline organoids can be cultured from fresh and frozen liver and from needle biopsy • A feline-specific liver culture medium allows organoid expansion up to 32 passages • When fed fatty acids, feline liver organoids store more lipids than human organoids • Feline liver organoids can be used to model hepatic steatosis, In this study Kruitwagen and colleagues establish and characterize a feline liver organoid culture, which has adult stem cell properties and can be differentiated toward hepatocyte-like cells. They propose liver organoids as a tool to model hepatic steatosis and show that feline liver organoids accumulate more lipids than human organoids when provided with excess fatty acids.

Published
2017

34. Characterization of Endothelial and Smooth Muscle Cells From Different Canine Vessels

Author

Oosterhoff, Loes A, Kruitwagen, Hedwig S, van Wolferen, Monique E, van Balkom, Bas W M, Mokry, Michal, Lansu, Nico, van den Dungen, Noortje A M, Penning, Louis C, Spanjersberg, Talitha C F, de Graaf, Johannes W, Veenendaal, Tomas, Zomerdijk, Flin, Fledderus, Joost O, Spee, Bart, van Steenbeek, Frank G, Biochemisch laboratorium, dCSCA RMSC-1, LS Interne geneeskunde, Sub Biomol.Mass Spect. and Proteomics, dCSCA AVR, Onderzoek, Undergraduate School, Biochemisch laboratorium, dCSCA RMSC-1, LS Interne geneeskunde, Sub Biomol.Mass Spect. and Proteomics, dCSCA AVR, Onderzoek, and Undergraduate School

Subjects
0301 basic medicine, Cell type, Vascular smooth muscle, Endothelium, Physiology, Angiogenesis, Biology, lcsh:Physiology, Transcriptome, 03 medical and health sciences, angiogenesis, 0302 clinical medicine, Tissue engineering, cell model system, vascular cell interaction, Physiology (medical), medicine, vascular smooth muscle cells, vascular smooth, Tissue homeostasis, Original Research, lcsh:QP1-981, Vascular disease, medicine.disease, endothelial cells, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, cardiovascular system
Abstract

Vasculature performs a critical function in tissue homeostasis, supply of oxygen and nutrients, and the removal of metabolic waste products. Vascular problems are implicated in a large variety of pathologies and accurate in vitro models resembling native vasculature are of great importance. Unfortunately, existing in vitro models do not sufficiently reflect their in vivo counterpart. The complexity of vasculature requires the examination of multiple cell types including endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), as well as vessel location in the body from which they originate. The use of canine blood vessels provides a way to study vasculature with similar vessel size and physiology compared to human vasculature. We report an isolation procedure that provides the possibility to isolate both the endothelial and smooth muscle cells from the same vessels simultaneously, enabling new opportunities in investigating vasculature behavior. Canine primary ECs and VSMCs were isolated from the vena cava, vena porta and aorta. All tissue sources were derived from three donors for accurate comparison and to reduce inter-animal variation. The isolation and purification of the two distinct cell types was confirmed by morphology, gene- and protein-expression and function. As both cell types can be derived from the same vessel, this approach allows accurate modeling of vascular diseases and can also be used more widely, for example, in vascular bioreactors and tissue engineering designs. Additionally, we identified several new genes that were highly expressed in canine ECs, which may become candidate genes for novel EC markers. In addition, we observed transcriptional and functional differences between arterial- and venous-derived endothelium. Further exploration of the transcriptome and physiology of arteriovenous differentiation of primary cells may have important implications for a better understanding of the fundamental behavior of the vasculature and pathogenesis of vascular disease.

Published
2019

35. Large-scale Production of LGR5-positive Bipotential Human Liver Stem Cells

Author

Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, Spee, Bart, Schneeberger, Kerstin, Sánchez-Romero, Natalia, Ye, Shicheng, van Steenbeek, Frank G, Oosterhoff, Loes A, Pla Palacin, Iris, Chen, Chen, van Wolferen, Monique E, van Tienderen, Gilles, Lieshout, Ruby, Colemonts-Vroninks, Haaike, Schene, Imre, Hoekstra, Ruurdtje, Verstegen, Monique M A, van der Laan, Luc J W, Penning, Louis C, Fuchs, Sabine A, Clevers, Hans, De Kock, Joery, Baptista, Pedro M, and Spee, Bart

Abstract

The gap between patients on transplant waiting lists and available donor organs is steadily increasing. Human organoids derived from Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)-positive adult stem cells represent an exciting new cell source for liver regeneration; however, culturing large numbers of organoids with current protocols is tedious and the level of hepatic differentiation is limited. Here, we established a new method for the expansion of large quantities of human liver organoids in spinner flasks. Due to improved oxygenation in the spinner flasks, organoids rapidly proliferated and reached an average 40-fold cell expansion after two weeks, compared to 6-fold expansion in static cultures. The organoids repopulated decellularized liver discs and formed liver-like tissue. After differentiation in spinner flasks, mature hepatocyte markers were highly upregulated compared to static organoid cultures, and cytochrome p450 activity reached levels equivalent to hepatocytes. CONCLUSION: We established a highly efficient method for culturing large numbers of LGR5-positive stem cells in the form of organoids, which paves the way for the application of organoids for tissue engineering and liver transplantation.

Published
2019

36. Characterization of Endothelial and Smooth Muscle Cells From Different Canine Vessels

Author

Biochemisch laboratorium, dCSCA RMSC-1, LS Interne geneeskunde, Sub Biomol.Mass Spect. and Proteomics, dCSCA AVR, Onderzoek, Undergraduate School, Oosterhoff, Loes A, Kruitwagen, Hedwig S, van Wolferen, Monique E, van Balkom, Bas W M, Mokry, Michal, Lansu, Nico, van den Dungen, Noortje A M, Penning, Louis C, Spanjersberg, Talitha C F, de Graaf, Johannes W, Veenendaal, Tomas, Zomerdijk, Flin, Fledderus, Joost O, Spee, Bart, van Steenbeek, Frank G, Biochemisch laboratorium, dCSCA RMSC-1, LS Interne geneeskunde, Sub Biomol.Mass Spect. and Proteomics, dCSCA AVR, Onderzoek, Undergraduate School, Oosterhoff, Loes A, Kruitwagen, Hedwig S, van Wolferen, Monique E, van Balkom, Bas W M, Mokry, Michal, Lansu, Nico, van den Dungen, Noortje A M, Penning, Louis C, Spanjersberg, Talitha C F, de Graaf, Johannes W, Veenendaal, Tomas, Zomerdijk, Flin, Fledderus, Joost O, Spee, Bart, and van Steenbeek, Frank G

Published
2019

37. Association of circulating microRNA-122 and microRNA-29a with stage of fibrosis and progression of chronic hepatitis in Labrador Retrievers

Author

dCSCA RMSC-1, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, LS Pathologie, PB AVM, Dep Pathobiologie, Applied Veterinary Research, dCSCA AVR, Sakai, Manabu, Spee, Bart, Grinwis, Guy C M, Penning, Louis C, van Wolferen, Monique E, van der Laan, Luc J W, Fieten, Hille, dCSCA RMSC-1, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, LS Pathologie, PB AVM, Dep Pathobiologie, Applied Veterinary Research, dCSCA AVR, Sakai, Manabu, Spee, Bart, Grinwis, Guy C M, Penning, Louis C, van Wolferen, Monique E, van der Laan, Luc J W, and Fieten, Hille

Published
2019

38. Characterization of endothelial and smooth muscle cells from different canine vessels

Author

UMC Utrecht, MS Nefrologie, Circulatory Health, Dagcentrum, Child Health, MDL onderzoek 1, Regenerative Medicine and Stem Cells, Oosterhoff, Loes A., Kruitwagen, Hedwig S., Van Wolferen, Monique E., Van Balkom, Bas W.M., Mokry, Michal, Lansu, Nico, Lansu, NR, Van Den Dungen, Noortje A.M., Penning, Louis C., Spanjersberg, Talitha C.F., De Graaf, Johannes W., Veenendaal, Tomas, Zomerdijk, Flin, Fledderus, Joost O., Spee, Bart, Van Steenbeek, Frank G., UMC Utrecht, MS Nefrologie, Circulatory Health, Dagcentrum, Child Health, MDL onderzoek 1, Regenerative Medicine and Stem Cells, Oosterhoff, Loes A., Kruitwagen, Hedwig S., Van Wolferen, Monique E., Van Balkom, Bas W.M., Mokry, Michal, Lansu, Nico, Lansu, NR, Van Den Dungen, Noortje A.M., Penning, Louis C., Spanjersberg, Talitha C.F., De Graaf, Johannes W., Veenendaal, Tomas, Zomerdijk, Flin, Fledderus, Joost O., Spee, Bart, and Van Steenbeek, Frank G.

Published
2019

39. DYRK1A Is a Regulator of S-Phase Entry in Hepatic Progenitor Cells

Author

Kruitwagen, Hedwig S., Westendorp, Bart, Viebahn, Cornelia S., Post, Krista, van Wolferen, Monique E., Oosterhoff, Loes A., Egan, David A., Delabar, Jean-Maurice, Toussaint, Mathilda J., Schotanus, Baukje A., de Bruin, Alain, Rothuizen, Jan, Penning, Louis C., Spee, Bart, dCSCA RMSC-1, Onderzoek, LS Pathobiologie, dPB RMSC, LS Interne geneeskunde, LS Algemene chirurgie, Biochemisch laboratorium, and dCSCA AVR

Subjects
proliferation, RNA interference screen, cell cycle, DYRK1A, hepatic progenitor cells
Abstract

Plant cells contain two major pools of K+, one in the vacuole and one in the cytosol. The behavior of K+ concentrations in these pools is fundamental to understand-ing the way this nutrient affects plantigrowth. Triple-barreled microelectrodes have been used to obtain the first fully quantitative measurements of the changes in K+ activity (ay) in the vacuole and cytosol of barley (Hordeum vulgare L.) root cells grown in different K+ concentrations. The electrodes incorporate a pH-selective barrel allowing each measurement to be assigned to either the cytosol or vacuole. The measure-ments revealed that vacuolar aK declined linearly with de-creases in tissue K+ concentration, whereas cytosolic aK initially remained constant in both epidermal and cortical cells but then declined at different rates in each cell type. An unexpected finding was that cytoplasmic pH declined in parallel with cytosolic aK, but acidification of the cytosol with butyrate did not reveal any short-term link between these two parameters. These measurements show the very different responses of the vacuolar and cytosolic K+ pools to changes in K+ availability and also show that cytosolic K+ homeostasis differs quantitatively in different cell types. The data have

Published
2018

41. DYRK1A Is a Regulator of S-Phase Entry in Hepatic Progenitor Cells

Author

Kruitwagen, Hedwig S., Westendorp, Bart, Viebahn, Cornelia S., Post, Krista, van Wolferen, Monique E., Oosterhoff, Loes A., Egan, David A., Delabar, Jean-Maurice, Toussaint, Mathilda J., Schotanus, Baukje A., de Bruin, Alain, Rothuizen, Jan, Penning, Louis C., Spee, Bart, dCSCA RMSC-1, Onderzoek, LS Pathobiologie, dPB RMSC, LS Interne geneeskunde, LS Algemene chirurgie, Biochemisch laboratorium, and dCSCA AVR

Subjects
0301 basic medicine, Small interfering RNA, Transcription, Genetic, proliferation, Biology, Protein Serine-Threonine Kinases, Cell Line, S Phase, 03 medical and health sciences, RNA interference screen, Organoid, Humans, Progenitor cell, E2F, hepatic progenitor cells, Cell Biology, Hematology, DYRK1A, Cell cycle, Protein-Tyrosine Kinases, Liver regeneration, Cell biology, Adult Stem Cells, 030104 developmental biology, Liver, Cell culture, cell cycle, Stem cell, Developmental Biology
Abstract

Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. One hit increased the percentage of EdU-positive cells after knockdown: dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Although upon DYRK1A silencing, the percentage of EdU- and phosphorylated histone H3 (pH3)-positive cells was increased, and total cell numbers were not increased, possibly through a subsequent delay in cell cycle progression. This phenotype was confirmed with chemical inhibition of DYRK1A using harmine and with primary HPCs cultured as liver organoids. DYRK1A inhibition impaired Dimerization Partner, RB-like, E2F, and multivulva class B (DREAM) complex formation in HPCs and abolished its transcriptional repression on cell cycle progression. To further analyze DYRK1A function in HPC proliferation, liver organoid cultures were established from mBACtgDyrk1A mice, which harbor one extra copy of the murine Dyrk1a gene (Dyrk+++). Dyrk+++ organoids had both a reduced percentage of EdU-positive cells and reduced proliferation compared with wild-type organoids. This study provides evidence for an essential role of DYRK1A as balanced regulator of S-phase entry in HPCs. An exact gene dosage is crucial, as both DYRK1A deficiency and overexpression affect HPC cell cycle progression.

Published
2017

42. Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times

Author

Rao Nagesha AS, van Wolferen Monique E, Kirpensteijn Jolle, Selvarajah Gayathri T, Fieten Hille, and Mol Jan A

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS. Results The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans. Conclusion A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.

Published
2009
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44. DYRK1A Is a Regulator of S-Phase Entry in Hepatic Progenitor Cells

Author

dCSCA RMSC-1, Onderzoek, LS Pathobiologie, dPB RMSC, LS Interne geneeskunde, LS Algemene chirurgie, Biochemisch laboratorium, dCSCA AVR, Kruitwagen, Hedwig S., Westendorp, Bart, Viebahn, Cornelia S., Post, Krista, van Wolferen, Monique E., Oosterhoff, Loes A., Egan, David A., Delabar, Jean-Maurice, Toussaint, Mathilda J., Schotanus, Baukje A., de Bruin, Alain, Rothuizen, Jan, Penning, Louis C., Spee, Bart, dCSCA RMSC-1, Onderzoek, LS Pathobiologie, dPB RMSC, LS Interne geneeskunde, LS Algemene chirurgie, Biochemisch laboratorium, dCSCA AVR, Kruitwagen, Hedwig S., Westendorp, Bart, Viebahn, Cornelia S., Post, Krista, van Wolferen, Monique E., Oosterhoff, Loes A., Egan, David A., Delabar, Jean-Maurice, Toussaint, Mathilda J., Schotanus, Baukje A., de Bruin, Alain, Rothuizen, Jan, Penning, Louis C., and Spee, Bart

Published
2018

45. Immunohistochemical evaluation of the activation of hepatic progenitor cells and their niche in feline lymphocytic cholangitis

Author

dCSCA RMSC-1, dCSCA AVR, Intensieve Zorgafdeling, Veterinair Pathologisch Diagnostisch Cnt, Biochemisch laboratorium, Sub Hepatologie, LS Interne geneeskunde, Onderzoek, Otte, Corma Ma, Valtolina, Chiara, Vreman, Sandra, Hubers, Siobhan, van Wolferen, Monique E, Favier, Robert P, Rothuizen, Jan, Penning, Louis C, dCSCA RMSC-1, dCSCA AVR, Intensieve Zorgafdeling, Veterinair Pathologisch Diagnostisch Cnt, Biochemisch laboratorium, Sub Hepatologie, LS Interne geneeskunde, Onderzoek, Otte, Corma Ma, Valtolina, Chiara, Vreman, Sandra, Hubers, Siobhan, van Wolferen, Monique E, Favier, Robert P, Rothuizen, Jan, and Penning, Louis C

Published
2018

46. Hepatocyte-like cells generated by direct reprogramming from murine somatic cells can repopulate decellularized livers

Author

Hubrecht Institute with UMC, Chen, Chen, Pla-Palacín, Iris, Baptista, Pedro M., Shang, Peng, Oosterhoff, Loes A., van Wolferen, Monique E., Penning, Louis C., Geijsen, Niels, Spee, Bart, Hubrecht Institute with UMC, Chen, Chen, Pla-Palacín, Iris, Baptista, Pedro M., Shang, Peng, Oosterhoff, Loes A., van Wolferen, Monique E., Penning, Louis C., Geijsen, Niels, and Spee, Bart

Published
2018

47. Cellular characteristics of keratin 19-positive canine hepatocellular tumours explain its aggressive behaviour

Author

van Sprundel, Renee G H M, van den Ingh, Ted Sgam, Schotanus, Baukje A, van Wolferen, Monique E, Penning, Louis C, Rothuizen, Jan, Spee, Bart, dB&C FR-RMSC FR, dCSCA AVR, Onderzoek, dCSCA RMSC-1, dB&C FR-RMSC FR, dCSCA AVR, Onderzoek, and dCSCA RMSC-1

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, canine, Malignancy, hepatocellular tumours, 03 medical and health sciences, 0302 clinical medicine, Growth factor receptor, Laminin, tumour markers, Keratin, medicine, Progenitor cell, Neurofibromatosis type 2, chemistry.chemical_classification, General Veterinary, biology, CD29, Companion or Pet Animals, medicine.disease, digestive system diseases, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, immunohistochemistry, biology.protein, Immunohistochemistry, malignancy
Abstract

The expression of the hepatic progenitor cell marker keratin 19 (K19) in canine hepatocellular carcinomas is linked with a poor prognosis. To better understand this aggressive behaviour, K19-positive hepatocellular carcinomas (n=5) and K19-negative hepatocellular adenomas (n=6) were immunohistochemically stained for proteins involved in malignant tumour development. The K19-positive carcinomas showed marked positivity for platelet-derived growth factor receptor alpha polypeptide (PDGFRα), laminin, integrin beta-1/CD29, B-cell-specific Moloney murine leukaemia virus Integration site 1, glypican-3 (GPC-3) and prominin-1/CD133, in contrast with K19-negative hepatocellular adenomas. Conversely, neurofibromatosis type 2 was highly expressed in the hepatocellular adenomas in contrast with the hepatocellular carcinomas. This expression pattern is clearly in line with the observed aggressive behaviour. The presence of the malignancy markers PDGFRα and GPC-3 might make it possible to develop specific strategies to intervene in tumour growth and to devise novel serological tests and personalised treatment methods for canine hepatocellular carcinomas.

Published
2017

48. Aberrant hepatic lipid storage and metabolism in canine portosystemic shunts

Author

Van den Bossche, Lindsay, Schoonenberg, Vivien A C, Burgener, Iwan A, Penning, Louis C, Schrall, Ingrid M, Kruitwagen, Hedwig S, van Wolferen, Monique E, Grinwis, Guy C M, Kummeling, Anne, Rothuizen, Jan, van Velzen, Jeroen F., Stathonikos, Nikolas, Molenaar, Martijn R, Helms, Bernd J, Brouwers, Jos F H M, Spee, Bart, van Steenbeek, Frank G, dCSCA RMSC-1, dCSCA AVR, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, dB&C FR-RMSC FR, dCSCA RMSC-1, dCSCA AVR, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, PB AVM, and dB&C FR-RMSC FR

Subjects
0301 basic medicine, Steatosis, lcsh:Medicine, Pathology and Laboratory Medicine, Biochemistry, Gastroenterology, Mass Spectrometry, Cytopathology, Pathogenesis, chemistry.chemical_compound, Non-alcoholic Fatty Liver Disease, Medicine and Health Sciences, Portasystemic Shunt, Surgical, Organ Cultures, lcsh:Science, Chromatography, High Pressure Liquid, Phospholipids, Mammals, Multidisciplinary, Agricultural and Biological Sciences(all), Liver Diseases, Fatty Acids, Fatty liver, Eukaryota, Lipids, Organoids, Liver, Vertebrates, Biological Cultures, Neutral Lipids, Shunt (electrical), Research Article, medicine.medical_specialty, Gastroenterology and Hepatology, Research and Analysis Methods, 03 medical and health sciences, Dogs, Internal medicine, medicine, Organoid, Animals, Triglyceride, Biochemistry, Genetics and Molecular Biology(all), business.industry, lcsh:R, Organisms, Biology and Life Sciences, Lipid metabolism, Metabolism, Lipid Metabolism, medicine.disease, Fatty Liver, 030104 developmental biology, chemistry, Anatomical Pathology, Amniotes, lcsh:Q, business, Genetics and Molecular Biology(all)
Abstract

Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model. Hepatic lipid accumulation, gene-expression analysis and HPLC-MS of neutral lipids and phospholipids in extrahepatic (EHPSS) and intrahepatic portosystemic shunts (IHPSS) was compared to healthy control dogs. Liver organoids of diseased dogs and healthy control dogs were incubated with palmitic- and oleic-acid, and lipid accumulation was quantified using LD540. In histological slides of shunt livers, a 12-fold increase of lipid content was detected compared to the control dogs (EHPSS P

Published
2017

49. Expression of the insulin-like growth factor (IGF) system and steroidogenic enzymes in canine testis tumors

Author

Oosterlaken-Dijksterhuis Marja A, van Wolferen Monique E, Mol Jan A, Peters Monique AJ, Teerds Katja J, and van Sluijs Frederik J

Subjects
Gynecology and obstetrics, RG1-991, Reproduction, QH471-489
Abstract

Abstract Testis tumors occur frequently in dogs. The main types of tumors are Sertoli cell tumors, seminomas, and Leydig cell tumors. Mixed tumors and bilateral occurrence of tumors may be encountered frequently. To elucidate the possible relationship between the insulin-like growth factor (IGF) system and the development of different types of testis tumors in dogs, the expression of insulin-like growth factor-I and II (IGF-I and IGF-II), their type I receptor (IGF-IR), and their binding proteins (IGFBPs) was examined. In addition the expression of the steroidogenic enzymes p450-aromatase and 5α-reductase type I and type II, and the androgen receptor (AR) was investigated by a semiquantitative reverse-transcriptase PCR (RT-PCR). Both normal testes and testes with tumors were studied. In normal testes a clear expression of IGF-I, IGF-II, IGF-IR, IGFBP2, IGFBP4 and IGFBP5 was found. Expression of IGFBP1 and IGFBP3 was weak. There was also clear expression of the steroidogenic enzymes 5α-reductase, aromatase, and the AR. Quantification of RT-PCR products revealed significantly less expression of IGFBP1, IGF-I, and 5α-reductase type I in Sertoli cell tumors and seminomas. Leydig cell tumors and mixed tumors had a significantly higher expression of IGFBP4 and IGF-IR than normal testes. The expression of aromatase was lower in seminomas and in mixed tumors. The expression of AR, IGF-II and IGFBP2, IGFBP3, IGFBP5, and 5α-reductase type II did not differ among the different types of tumors. It was concluded that Sertoli cell tumors and seminomas have a comparable expression of the IGF system while Leydig cell tumors have a different pattern, suggesting difference in pathobiology among these types of tumors.

Published
2003
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50. Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis.

Author

Valtolina, Chiara, Robben, Joris H, van Wolferen, Monique E, Kruitwagen, Hedwig S, Corbee, Ronald J, Favier, Robert P, and Penning, Louis C

Abstract

Objectives: The aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL). Methods: Lipogenic gene expression of peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor-gamma (PPAR-γ), fatty acid synthase (FASN) and sterol regulatory element-binding factor (SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats. Results: In liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different (P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group (P = 0.039). Conclusions and relevance: The downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL. [ABSTRACT FROM AUTHOR]

Published
2020
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