Stem Cell Therapies for Treatment of Liver Disease.

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways.

Portal hypertension correlates with splenic stiffness as measured with MR elastography.

Purpose: To investigate the correlation between MR elastography (MRE) assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension.

Materials And Methods: Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based echo planar imaging (EPI) MRE sequence was used to acquire three-dimensional/three axis (3D/3-axis) abdominal MRE data at baseline, 4 weeks, and 8 weeks.

Normal atmospheric oxygen tension and the use of antioxidants improve hepatocyte spheroid viability and function.

Hepatocyte spheroids have been proposed for drug metabolism studies and in bioartificial liver devices. However, the optimal conditions required to meet the aerobic demands of mitochondria-rich hepatocyte spheroids is not well studied. We hypothesized that an optimal concentration of oxygen could be identified and that the health of hepatocyte spheroids might be further improved by antioxidant therapy.

E-cadherin protects primary hepatocyte spheroids from cell death by a caspase-independent mechanism.

Cultivation of primary hepatocytes as spheroids creates an efficient three-dimensional model system for hepatic studies in vitro and as a cell source for a spheroid reservoir bioartificial liver. The mechanism of spheroid formation is poorly understood, as is an explanation for why normal, anchorage-dependent hepatocytes remain viable and do not undergo detachment-induced apoptosis, known as anoikis, when placed in suspension spheroid culture. The purpose of this study was to investigate the role of E-cadherin, a calcium-dependent cell adhesion molecule, in the formation and maintenance of hepatocyte spheroids.

Optimization of mass transfer for toxin removal and immunoprotection of hepatocytes in a bioartificial liver.

This study was designed to determine optimal operating conditions of a bioartificial liver (BAL) based on mass transfer of representative hepatotoxins and mediators of immune damage. A microprocessor-controlled BAL was used to study mass transfer between patient and cell compartments separated by a hollow fiber membrane. Membrane permeability (70, 150, or 400 kDa molecular weight cut-off-MWCO), membrane convection (high: 50 mL/min; medium: 25 mL/min; low: 10 mL/min; diffusion: 0 mL/min), and albumin concentration in the cell compartment (0.

Gene expression and functional analyses of primary rat hepatocytes on nanofiber matrices.

Long term culture of primary hepatocytes is valuable for diagnostic and therapeutic applications. However, standard monolayer culture of primary hepatocytes on tissue culture plastic (TCP) - either uncoated or coated with a biological material such as collagen or laminin - is problematic. Thus, novel support matrices are under development to better maintain gene expression and differentiated function of primary hepatocytes in vitro.

Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function.

Unlabelled: The culture of primary hepatocytes as spheroids creates an efficient three-dimensional tissue construct for hepatic studies in vitro. Spheroids possess structural polarity and functional bile canaliculi with normal differentiated function. Thus, hepatocyte spheroids have been proposed as the cell source in a variety of diagnostic, discovery, and therapeutic applications, such as a bioartificial liver.

Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H.

Unlabelled: Loss of the nuclear hormone receptor hepatocyte nuclear factor 4alpha (HNF4alpha) in hepatocytes results in a complex pleiotropic phenotype that includes a block in hepatocyte differentiation and a severe disruption to liver function. Recent analyses have shown that hepatic gene expression is severely affected by the absence of HNF4alpha, with expression of 567 genes reduced by > or =2.5-fold (P < or = 0.

GATA6 is essential for embryonic development of the liver but dispensable for early heart formation.

Several lines of evidence suggest that GATA6 has an integral role in controlling development of the mammalian liver. Unfortunately, this proposal has been impossible to address directly because mouse embryos lacking GATA6 die during gastrulation. Here we show that the early embryonic deficiency associated with GATA6-knockout mice can be overcome by providing GATA6-null embryos with a wild-type extraembryonic endoderm with the use of tetraploid embryo complementation.