Improvement of Hepatocyte Transplantation Efficiency in the mdr2–/– Mouse Model by Glyceryl Trinitrate

Boudechiche, Lyes; Tranchart, Hadrien; Branchereau, Sophie; Davit–Spraul, Anne; Laïnas, Panagiotis; Groyer-Picard, Marie-Thérèse; Weber, Anne; Hadchouel, Michelle; Dagher, Ibrahim

doi:10.1097/tp.0000000000000463

Cited by 10 publications

(8 citation statements)

References 21 publications

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“…Among these individuals, two patients with PFIC2 showed no obvious benefits after hepatocyte transplantation, as the existing fibrosis impaired the engraftment of the transplanted hepatocytes [ 122 ]. Recently, glyceryl trinitrate have been shown to enhance the efficacy of the transplanted hepatocyte repopulation in Mdr2 knockout mice [ 124 ]. With additional treatment to boost donor cell repopulation, hepatocyte transplantation might be refined and benefit patients with cholestasis.…”

Section: Main Textmentioning

confidence: 99%

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

et al. 2018

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BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

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Section: Main Textmentioning

confidence: 99%

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

et al. 2018

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“…Although liver transplantation is considered as an ultimate treatment for various liver diseases, such as acute liver failure and end-stage liver disease (Boudechiche et al 2015), it is actually limited in the clinical practice owing to the severe shortage of donor liver organs. At present, several novel approaches, including hepatocyte transplantation and bioartificial liver support system, are being developed to replace the non-functioning liver of those patients waiting for liver transplantation with the aim of improving survival and preventing severe complications (Chen et al 2012;Hughes et al 2008;Lee et al 2016;Rohn et al 2016;Shi et al 2016;Struecker et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Co-culture system of hepatocytes and endothelial cells: two in vitro approaches for enhancing liver-specific functions of hepatocytes

et al. 2018

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Although hepatocyte transplantation and bioartificial liver support system provide new promising opportunities for those patients waiting for liver transplantation, hepatocytes are easily losing liver-specific functions by using the common in vitro cultured methods. The co-culture strategies with mimicking the in vivo microenvironment would facilitate the maintenance of liver-specific functions of hepatocytes. Considering that hepatocytes and endothelial cells (ECs) account for 80-90% of total cell populations in the liver, hepatocytes and ECs were directly co-cultured with hepatic stellate cells (HSCs) or adipose tissue-derived stem cells (ADSCs) at a ratio of 700:150:3 or 14:3:3 in the present study, and the liver-specific functions were carefully analyzed. Our results showed that the two co-culture systems presented the enhanced liver-specific functions through promoting secretion of urea and ALB and increasing the expressions of ALB, CYP3A4 and HNF4α, and the vessel-like structure in the co-culture system consisted of hepatocytes, ECs and ADSCs. Hence, our results suggested that the directly co-culture of hepatocytes and ECs with HSCs or ADSCs could significantly improve liver-specific functions of hepatocytes, and the co-culture system could further promote angiogenesis of ECs at a later stage. Therefore, this study provides potential interesting in vitro strategies for enhancing liver-specific functions of hepatocytes.

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“…Multiple studies, both clinically and preclinically, have aimed to improve the efficacy of HTx therapy (Boudechiche et al., 2015; Nagamoto et al., 2016, 2014; Soltys et al., 2017; Yamanouchi et al., 2009). Typically, analyses of HTx engraftment are restricted to serial biopsies and/or serum samples without the involvement of non-invasive monitoring.…”

Section: Discussionmentioning

confidence: 99%

Reporter gene-engineering of human induced pluripotent stem cells during differentiation renders in vivo traceable hepatocyte-like cells accessible

et al. 2019

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Improvement of Hepatocyte Transplantation Efficiency in the mdr2–/– Mouse Model by Glyceryl Trinitrate

Abstract: The use of GTN improves hepatocyte engraftment and correction of metabolic disease in mdr2 (-/-) mice. This approach might be beneficial in hepatocyte transplantation for the treatment of patients with liver diseases.

Cited by 10 publications

References 21 publications

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Co-culture system of hepatocytes and endothelial cells: two in vitro approaches for enhancing liver-specific functions of hepatocytes

Reporter gene-engineering of human induced pluripotent stem cells during differentiation renders in vivo traceable hepatocyte-like cells accessible

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