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Open AccessArticle

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

1
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
2
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
3
Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
4
Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center, Utrecht University, 3584 CT Utrecht, The Netherlands
5
Hubrecht Organoid Technology (HUB), 3584 CT Utrecht, The Netherlands
*
Authors to whom correspondence should be addressed.
Present address: Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
Present address: LifeCareCure-Impuls, 3983 PS, Odijk, The Netherlands
§
These authors contributed equally to this work
Cells 2020, 9(2), 410; https://doi.org/10.3390/cells9020410
Received: 20 December 2019 / Revised: 29 January 2020 / Accepted: 30 January 2020 / Published: 11 February 2020
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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.
Keywords: dog; copper; organoids; transplantation; autologous; hepatocytes; cell transplantation; Wilson’s disease dog; copper; organoids; transplantation; autologous; hepatocytes; cell transplantation; Wilson’s disease
MDPI and ACS Style

Kruitwagen, H.S.; Oosterhoff, L.A.; van Wolferen, M.E.; Chen, C.; Nantasanti Assawarachan, S.; Schneeberger, K.; Kummeling, A.; van Straten, G.; Akkerdaas, I.C.; Vinke, C.R.; van Steenbeek, F.G.; van Bruggen, L.W.; Wolfswinkel, J.; Grinwis, G.C.; Fuchs, S.A.; Gehart, H.; Geijsen, N.; Vries, R.G.; Clevers, H.; Rothuizen, J.; Schotanus, B.A.; Penning, L.C.; Spee, B. Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease. Cells 2020, 9, 410.

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