Histidinemia in mice: A metabolic defect treated using a novel approach to hepatocellular transplantation

Abstract

Histidinemia in mice and in humans is an autosomal recessive disorder of histidine metabolism that leads to high-histidine levels in both plasma and urine and is caused by a lack of hepatic histidine-alpha-deaminase (histidase). We have used a novel approach to hepatocellular transplantation to effect a complete phenotypic cure of histidinemia in a mouse model. Mice lacking histidase were treated with isolated liver cells (approximately 18 x 10(6) hepatocytes and 9 x 10(6) nonparenchymal cells) from histidase-competent donors transplanted into the peritoneum (active transplant group). Recipient mice showed a dramatic decrease, by more than 75%, in urinary histidine levels from day one throughout the course of the experiment, resulting in levels within the normal range for wild-type mice. In comparison, there was no change in urinary histidine levels in the control group of histidase-deficient mice treated with isolated liver cells from mice lacking histidase (statistical comparison between the two groups, P < .003, two-way ANOVA). Histologically, ectopic liver tissue was seen in the peritoneum in association with abdominal wall, pancreas, and peritoneal connective tissue; immunohistochemical evidence showed expression of histidase in the ectopic liver tissue in the active transplant group. This report is the first to show complete correction of a defective biochemical phenotype achieved by hepatocellular transplantation.

The Liver Vascular Bed for Hepatocytes Cell Therapy and Tissue Engineering

“…The vascular growth and remodeling is very much dependent on growth factors and extracellular matrix components. A beneficial effect of co-transplantation with non parenchymal cell has been shown before (Selden et al 1995). When hepatocytes formed spheroids they kept their function within the matrices for a longer period of time (Lin and Bissell.…”

“…Attachment to collagen-coated beads or microencapsulation allowed for only minimal improvement (Selden et al 2003;Baldini et al 2008). Co transplantation with non parenchymal cells showed some promise yet, hepatocytes transplanted to the peritoneum or dorsal fat pad do not express genes as those transplanted in the liver (Gupta et al 1994;Selden et al 1995). To overcome the problems of intraportal transplantation in the advanced cirrhotic liver with portal hypertension, transplantation into an extrahepatic site is necessary.…”

Fetal liver cell transplantation as a potential alternative to whole liver transplantation?

“…In subsequent studies, primary hepatocytes were infused into other ectopic sites, e.g., the dorsal fascia [14] or spleen [15], and the potential of transplanted hepatocytes was investigated in several animal disease models, e.g., rats with surgically induced acute liver failure [16], Watanabe heritable hyperlipidemic rabbits [17,18], histidinemic mice [19,20], hyperuricemic Dalmatian coach dogs [21,22], and LongEvans cinnamon rats (a model for Wilson's disease) [23,24]. These reports showed reduced mortality rates after cell transplantation [16,24], or a temporary [18,22] or complete correction [20] of defective biochemical phenotypes by hepatocyte transplantation.…”

Liver cells: biology to therapeutics

“…We have investigated the mouse model of histidinaemia, a single amino acid substitution in a hepatic cytosolic enzyme that leads to elevated serum and urine histidine. 10 There is a similar condition in man, usually symptomless although some problems with speech and higher mental function have been associated. The biochemical hallmark of the disease, elevated urinary histidine, was returned to normal by intraperitoneal injection of less than 5% equivalent of normal hepatocytes.…”