Prospective observational and analytic study. To investigate whether spontaneous intervertebral disc degeneration (IVDD) occurring in both chondrodystrophic (CD) and nonchondrodystrophic dogs (NCD) can be used as a valid translational model for human IVDD research. Different animal models are used in IVDD research, but in most of these models IVDD is induced manually or chemically rather than occurring spontaneously. A total of 184 intervertebral discs (IVDs) from 19 dogs of different breeds were used. The extent of IVDD was evaluated by macroscopic grading, histopathology, glycosaminoglycan content, and matrix metalloproteinase 2 activity. Canine data were compared with human IVD data acquired in this study or from the literature. Gross pathology of IVDD in both dog types (CD and NCD) and humans showed many similarities, but the cartilaginous endplates were significantly thicker and the subchondral cortices significantly thinner in humans than in dogs. Notochordal cells were still present in the IVDs of adult NCD but were not seen in the CD breeds or in humans. Signs of degeneration were seen in young dogs of CD breeds (<1 year of age), whereas this was only seen in older dogs of NCD breeds (5–7 years of age). The relative glycosaminoglycan content and metalloproteinase 2 activity in canine IVDD were similar to those in humans: metalloproteinase 2 activity increased and glycosaminoglycan content decreased with increasing severity of IVDD. IVDD is similar in humans and dogs. Both CD and NCD breeds may therefore serve as models of spontaneous IVDD for human research. However, as with all animal models, it is important to recognize interspecies differences and, indeed, the intraspecies differences between CD and NCD breeds (early vs. late onset of IVDD, respectively) to develop an optimal canine model of human IVDD.

The recent development of 3D-liver stem cell cultures (hepatic organoids) opens up new avenues for gene and/or stem cell therapy to treat liver disease. To test safety and efficacy, a relevant large animal model is essential but not yet established. Because of its shared pathologies and disease pathways, the dog is considered the best model for human liver disease. Here we report the establishment of a long-term canine hepatic organoid culture allowing undifferentiated expansion of progenitor cells that can be differentiated toward functional hepatocytes. We show that cultures can be initiated from fresh and frozen liver tissues using Tru-Cut or fine-needle biopsies. The use of Wnt agonists proved important for canine organoid proliferation and inhibition of differentiation. Finally, we demonstrate that successful gene supplementation in hepatic organoids of COMMD1-deficient dogs restores function and can be an effective means to cure copper storage disease.

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.