Abstract
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.
Highlights
The increasing shortage of donor organs and the morbidity and mortality associated with liver transplantation and subsequent immune suppression underscore the urgent need for novel treatments for patients with liver disease
Patient-specific canine COMMD1-deficient organoids were successfully cultured from liver biopsies (Figure 1A, Figure S3A)
We confirmed the presence of the COMMD1 protein in liver organoids after transduction by immunocytochemistry (Figure S3C) and induced organoid differentiation after expansion by changing medium composition from expansion medium (EM) to differentiation medium (DM) [23]
Summary
The increasing shortage of donor organs and the morbidity and mortality associated with liver transplantation and subsequent immune suppression underscore the urgent need for novel treatments for patients with liver disease. Liver cell transplantation can be a less invasive alternative to liver transplantation, especially in cases of metabolic liver diseases. Partial liver repopulation with healthy hepatocytes has been successful for human Crigler–Najjar syndrome, phenylketonuria and urea cycle defects [1,2,3,4]. The transplanted hepatocytes, were obtained from a donor liver and recipients required lifelong immunosuppression. Primary hepatocytes do not proliferate in vitro and rapidly lose essential hepatocyte functions in culture [5,6]. The effect of hepatocyte transplantations is lost after months, putatively due to the limited lifespan of hepatocytes [7]
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