Major HGF-mediated regenerative pathways are similarly affected in human and canine cirrhosis

Spee, Bart; Arends, Brigitte; Ingh, T S van den; Roskams, Tania; Rothuizen, J.; Penning, Louis C.

doi:10.1186/1476-5926-6-8

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…Progressive liver disease is an ailment common to both humans and dogs, and the regulatory pathways involved in chronic fibrotic liver disease, which ultimately leads to liver cirrhosis, are the same in both species [22]–[24]. Impaired hepatic perfusion plays an important part in the chronic deterioration of liver function seen in progressive liver disease [25]–[27].…”

Section: Introductionmentioning

confidence: 99%

Aberrant Gene Expression in Dogs with Portosystemic Shunts

et al. 2013

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Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in IHPSS and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy.

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Section: Introductionmentioning

confidence: 99%

Aberrant Gene Expression in Dogs with Portosystemic Shunts

et al. 2013

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“…These are important advantages over rodent models, in which repeated liver biopsies for autologous organoid culture, cell tracking and safety evaluation are not feasible. Moreover, our dogs represent a highly relevant animal model, because essential molecular pathways and cells that contribute to regeneration are similar in dogs and humans with naturally occurring liver disease [15][16][17]. Hence, preclinical studies with autologous canine liver organoid transplantation will likely have a high predictive value for the safety and efficacy of autologous human liver organoid transplantations.…”

Section: Discussionmentioning

confidence: 99%

“…Dogs have naturally occurring liver diseases and mechanisms of canine liver disease and regeneration show striking similarities with humans on both a molecular and cellular level [15][16][17]. Canine copper storage disease is caused by a deletion of exon 2 of the copper metabolism domain containing 1 (COMMD1) gene that results in impaired copper excretion from hepatocytes into the bile [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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

Kruitwagen

Oosterhoff

Wolferen

et al. 2020

Cells

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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.

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“…For the investigation of several human diseases (69–71), including liver diseases (72, 73), the dog has been suggested as an important model. Dogs are subjected to the same environmental circumstances and suffer from clinically and biochemically comparable liver diseases that are not experimentally induced, in contrast to rodent models (72, 73). In addition, because of specialised veterinary medical care, the clinical and pathological evaluation of canine liver diseases also occurs at the same level as in humans.…”

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confidence: 99%