TY - JOUR
T1 - Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a COMMD1-Deficient Dog Model of Metabolic Liver Disease
AU - Kruitwagen, Hedwig S
AU - Oosterhoff, Loes A
AU - van Wolferen, Monique E
AU - Chen, Chen
AU - Nantasanti Assawarachan, Sathidpak
AU - Schneeberger, Kerstin
AU - Kummeling, Anne
AU - van Straten, Giora
AU - Akkerdaas, Ies C
AU - Vinke, Christel R
AU - van Steenbeek, Frank G
AU - van Bruggen, Leonie W L
AU - Wolfswinkel, Jeannette
AU - Grinwis, Guy C M
AU - Fuchs, Sabine A
AU - Gehart, Helmuth
AU - Geijsen, Niels
AU - Vries, Robert G
AU - Clevers, Hans
AU - Rothuizen, Jan
AU - Schotanus, Baukje A
AU - Penning, Louis C
AU - Spee, Bart
PY - 2020/2/11
Y1 - 2020/2/11
N2 - 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.
AB - 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.
U2 - 10.3390/cells9020410
DO - 10.3390/cells9020410
M3 - Article
C2 - 32053895
SN - 2073-4409
VL - 9
JO - Cells
JF - Cells
IS - 2
ER -