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

Cells

MoniqueE. van Wolferen¹  FrankG. van Steenbeek¹  Niels Geijsen¹  Bart Spee¹  Kerstin Schneeberger¹  Giora van Straten¹  Jan Rothuizen¹  BaukjeA. Schotanus¹  LeonieW.L. van Bruggen¹  IesC. Akkerdaas¹  ChristelR. Vinke¹  Anne Kummeling¹  Chen Chen¹  Sathidpak Nantasanti Assawarachan¹  Jeannette Wolfswinkel¹  LouisC. Penning¹  LoesA. Oosterhoff¹  HedwigS. Kruitwagen¹  GuyC.M. Grinwis²  SabineA. Fuchs³  Hans Clevers⁴  Helmuth Gehart⁴  RobertG. Vries⁵ 

[1] Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands;Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;Division of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands;Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center, Utrecht University, 3584 CT Utrecht, The Netherlands;Hubrecht Organoid Technology (HUB), 3584 CT Utrecht, The Netherlands;

关键词: dog;    copper;    organoids;    transplantation;    autologous;    hepatocytes;    cell transplantation;    wilson’s disease;   

DOI  :  10.3390/cells9020410

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown