The canine hepatic progenitor cell niche: Molecular characterisation in health and disease

Kruitwagen, Hedwig S.; Spee, Bart; Viebahn, Cornelia S.; Venema, H B; Penning, Louis C.; Grinwis, Guy C. M.; Favier, Robert P.; Ingh, T.S.G.A.M. van den; Rothuizen, J.; Schotanus, Baukje A

doi:10.1016/j.tvjl.2014.05.024

Cited by 12 publications

(23 citation statements)

References 44 publications

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“…These data show that both Wnt/β-catenin and Notch signalling are enhanced in activated HPC niches in dogs with LDH. The previous descriptions of the cellular constituents of the canine HPC niche and the current investigation on specific signalling cascades clearly show the similarities with other mammals, including human [ 12 , 13 ]. It is therefore conceivable that results of clinical approaches in human medicine will be applicable and beneficial in veterinary health care.…”

Section: Introductionsupporting

confidence: 62%

“…Liver samples were obtained from privately owned dogs with LDH (n = 4; age range 1.5-2.5 years), a rapidly progressing disease characterized by diffuse inflammation, peri-cellular fibrosis and massive HPC activation [ 12 , 13 ]. Informed consent was obtained as required under Dutch legislation.…”

Section: Methodsmentioning

confidence: 99%

“…This prompted the present focus on these two transmembrane signalling pathways in the activation of HPCs in canine liver diseases. Since lobular dissecting hepatitis (LDH) was previously observed to contain the highest number of activated HPCs, the activated HPC niche from LDH was microdissected and molecular analyses were performed in comparison with quiescent HPC niches harboured adjacent to portal areas of normal canine liver [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Wnt/β-catenin and Notch signalling in the activated canine hepatic progenitor cell niche

Schotanus

Kruitwagen

Ingh³

et al. 2014

BMC Vet Res

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BackgroundThe liver has a large regenerative capacity. Hepatocytes can replicate and regenerate a diseased liver. However, as is the case in severe liver diseases, this replication may become insufficient or exhausted and hepatic progenitor cells (HPCs) can be activated in an attempt to restore liver function. Due to their bi-potent differentiation capacity, these HPCs have great potential for regenerative approaches yet over-activation does pose potential health risks. Therefore the mechanisms leading to activation must be elucidated prior to safe implementation in the veterinary clinic. Wnt/β-catenin and Notch signalling have been implicated in the activation of HPCs in mouse models and in humans. Here we assessed the involvement in canine HPC activation. Gene-expression profiles were derived from laser microdissected HPC niches from lobular dissecting hepatitis (LDH) and normal liver tissue, with a focus on Wnt/β-catenin and Notch signalling. Immunohistochemical and immunofluorescent studies were combined to assess the role of the pathways in HPCs during LDH.ResultsGene-expression confirmed higher expression of Wnt/β-catenin and Notch pathway components and target genes in activated HPC niches in diseased liver compared to quiescent HPC niches from normal liver. Immunofluorescence confirmed the activation of these pathways in the HPCs during disease. Immunohistochemistry showed proliferating HPCs during LDH, and double immunofluorescence showed downregulation of Wnt/β-catenin and Notch in differentiating HPCs. Vimentin, a mesenchymal marker, was expressed on a subset of undifferentiated HPCs.ConclusionsTogether these studies clearly revealed that both Wnt/β-catenin and Notch signalling pathways are enhanced in undifferentiated, proliferating and potentially migrating HPCs during severe progressive canine liver disease (LDH).

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Section: Introductionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced Wnt/β-catenin and Notch signalling in the activated canine hepatic progenitor cell niche

Schotanus

Kruitwagen

Ingh³

et al. 2014

BMC Vet Res

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“…A specific adult liver stem cell population acting as second line of defense in liver regeneration has been described in several species, including rodents, humans, canines, and felines (Wang et al., 2003, Roskams et al., 2003, Kruitwagen et al., 2014, Ijzer et al., 2009). Recently, a three-dimensional and highly proliferative organoid culture system was developed for mouse, human, and dog liver stem cells (Huch et al., 2013, Huch et al., 2015, Nantasanti et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

et al. 2017

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SummaryHepatic 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.

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“…The presence and activation of liver progenitor cells was based on experimental mouse models, and ductular reactions (proliferation of intrahepatic bile ducts) were described in various diseases in humans [58][59][60][61][62][63]. Our initial papers described the activation of liver stem cells in canine hepatopathies and compared these patterns to the observation in human hepatopathies [64][65][66][67].…”

Section: Requirement 3 Culture Of Sufficient Quantities Of Commd1-fumentioning

confidence: 99%

Towards Bioengineered Liver Stem Cell Transplantation Studies in a Preclinical Dog Model for Inherited Copper Toxicosis

2019

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Wilson Disease is a rare autosomal recessive liver disorder in humans. Although its clinical presentation and age of onset are highly variable, hallmarks include signs of liver disease, neurological features and so-called Kayser-Fleischer rings in the eyes of the patient. Hepatic copper accumulation leads to liver disease and eventually to liver cirrhosis. Treatment options include life-long copper chelation therapy and/or decrease in copper intake. Eventually liver transplantations are indicated. Although clinical outcome of liver transplantations is favorable, the lack of suitable donor livers hampers large numbers of transplantations. As an alternative, cell therapies with hepatocytes or liver stem cells are currently under investigation. Stem cell biology in relation to pets is in its infancy. Due to the specific population structure of dogs, canine copper toxicosis is frequently encountered in various dog breeds. Since the histology and clinical presentation resemble Wilson Disease, we combined genetics, gene-editing, and matrices-based stem cell cultures to develop a translational preclinical transplantation model for inherited copper toxicosis in dogs. Here we describe the roadmap followed, starting from the discovery of a causative copper toxicosis mutation in a specific dog breed and culminating in transplantation of genetically-engineered autologous liver stem cells.

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The canine hepatic progenitor cell niche: Molecular characterisation in health and disease

Cited by 12 publications

References 44 publications

Enhanced Wnt/β-catenin and Notch signalling in the activated canine hepatic progenitor cell niche

Enhanced Wnt/β-catenin and Notch signalling in the activated canine hepatic progenitor cell niche

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Towards Bioengineered Liver Stem Cell Transplantation Studies in a Preclinical Dog Model for Inherited Copper Toxicosis

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