Hepatocellular Transplantation for Metabolic Deficiencies: Decrease of Plasma Bilirubin in Gunn Rats

Matas, A. J.; De, Sutherland; Mw, Steffes; Mauer, S. Michael; Sowe, A; Simmons, R L; Najarian, J S

doi:10.1126/science.818706

Cited by 286 publications

(110 citation statements)

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“…Transportation of hepatocytes (1)(2)(3), injection of hepatocyte extracts (1), and hepatocyte culture supernatants have been reported to prolong survival of rats with D(+)-galactosamine-induced liver injury (4) and animals with acute liver ischemia (5). Because homozygous Gunn rats lack UDP-glucuronosyltransferase activity for bilirubin, they cannot efficiently excrete bilirubin and, thus, exhibit lifelong nonhemolytic unconjugated hyperbilirubinemia (6)(7)(8). Hepatocyte transplantation has been used to impart the transferase activity in Gunn rats (9,10).…”

mentioning

confidence: 99%

Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats.

Demetriou

Levenson

Novikoff

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

134

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Hepatocytes harvested by collagenase perfusion of rat liver were attached to collagen-coated microcarriers and injected intraperitoneally into congeneic or allogeneic bilirubin-UDP-glucuronosyltransferase (EC 2.4.1.17)-deficient (Gunn) rats or allogeneic analbuminemic (NAR) rats. Five days later, the microcarriers were observed to have formed conglomerates chiefly on the anterior surface of the pancreas. Scanning electron microscopy showed hepatocytes attached to the granular collagen-coated surface of the microcarriers and newly formed connective tissue. Light microscopy revealed that the microcarriers formed a lattice with the collagen tissue; hepatocytes were seen within this lattice or on the surface of the microcarriers. Hepatocyte plasma membranes were nucleoside-diphosphatase (NDPase)-positive. Newly formed blood islands, blood vessels containing erythrocytes and leukocytes and NDPase-positive endothelium were observed in close proximity to the hepatocytes and fibroblasts. Transmission electron microscopic examination showed hepatocytes with microvilli and nucleoid-containing peroxisomes with catalase activity. Hepatocytes were present for up to 2 months in congeneic recipients, the longest period of observation after transplantation. After normal microcarrierattached hepatocytes were transplanted into allogeneic Gunn rats, bilirubin glucuronides were present in bile for 6 days. When congeneic Gunn rat recipients were used, bilirubin glucuronides were present in bile throughout the study (28 days); this was accompanied by reduction of serum bilirubin concentrations to nearly normal levels. After injection of normal hepatocytes into allogeneic NAR rats, plasma albumin concentration progressively increased for 6 days and then declined. In NAR recipients which were immunosuppressed with cyclosporin A, peak plasma albumin levels were reached in 14 days and persisted nearly at that level throughout the study (28 days). We describe a technique in which isolated rat hepatocytes, attached to collagen-coated dextran microcarriers, were injected i.p. in homozygous Gunn rats and genetically analbuminemic (NAR) rats. The injected microcarrierattached hepatocytes form conglomerates in the peritoneal cavity. Light and electron microscopic examination of the conglomerates showed differentiated hepatocytes, newly formed blood vessels, and fibroblasts. Function of the transplanted hepatocytes was shown in Gunn rats by biliary excretion of conjugated bilirubin and reduction of serum bilirubin concentration and in NAR rats by the appearance of albumin in the plasma. MATERIALS AND METHODSMale Wistar rats (200-250 g) were purchased from Charles River Breeding Laboratories. Syngeneic Wistar (RHA) rats and congeneic Gunn rats, which have identical genetic make-up with the Wistar (RHA) rats except for the bilirubin conjugation locus, were developed by C. Hansen of the National Institutes of Health and maintained as congeneic strains at the Albert Einstein College of Medicine (Bronx, NY). Analbuminemic (NAR) rats, mutants...

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mentioning

confidence: 99%

Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats.

Demetriou

Levenson

Novikoff

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

134

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“…Therefore the easiest disorders to correct are those which respond well to replacement of a relatively small portion of liver by cells bearing functional gene. In such cases, terminally differentiated hepatocytes may be useful for cell-based enzyme replacement One of the earlier records of such an experimental treatment was detailed in the 1976 article by Matas et al using the rat model of Crigler-Najjar Syndrome, (familial hyperbilirubinemia) (25). When immunosuppressed Gunn rats lacking the enzyme uridine diphosphate glucuronyltransferase were infused with normal hepatocytes via the portal vein, plasma bilirubin concentrations stably decreased, ameliorating clinical symptoms of the disease (25).…”

Section: Hepatocyte Transplantationmentioning

confidence: 99%

“…In such cases, terminally differentiated hepatocytes may be useful for cell-based enzyme replacement One of the earlier records of such an experimental treatment was detailed in the 1976 article by Matas et al using the rat model of Crigler-Najjar Syndrome, (familial hyperbilirubinemia) (25). When immunosuppressed Gunn rats lacking the enzyme uridine diphosphate glucuronyltransferase were infused with normal hepatocytes via the portal vein, plasma bilirubin concentrations stably decreased, ameliorating clinical symptoms of the disease (25). The viability of this procedure was verified a year later when Groth et al reproduced the curative effect of mature hepatocyte transplantation in the same animal model (26).…”

Section: Hepatocyte Transplantationmentioning

confidence: 99%

Stem cell therapy for inherited metabolic disorders of the liver

Ellor

Shupe

Petersen

2008

Experimental Hematology

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Modern medicine has conquered an enormous spectrum of health concerns, from the neonatal to the geriatric, the chronically ill to the acutely injured. Among the unmet challenges remaining in modern medicine are inborn disorders of metabolism within the liver. Such inherited metabolic disorders (IMDs) often leave an otherwise healthy individual with a crippling imbalance. As the principal regulator of the bodies many metabolic pathways, mal-encoded hepatic enzymes can drastically disrupt homeostasis throughout the entire body. Severe phenotypes are usually detected within the first few days of life, and treatments range from palliative lifestyle modifications, to aggressive surgical procedures. While orthotopic liver transplant is the single last resort 'cure' for these conditions, research over the past few years has brought new therapeutic technologies ever closer to the clinic. Stem cells, therapeutic viral vectors, or a combination thereof are projected to be the next, best, and final cure for IMDs, which is well reflected by this generation's research initiatives.

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“…More elaborate bioreactors have been designed to furnish stretch to skeletal muscle cultures (Vandenburgh et al 1997), shear to endothelial cells (Wang et al 1996) or compression to chondrocytes (Buckley et al 1998). There is good evidence that engineered tissues grown under physiological conditions including strain and pericellular nutrient availability have improved cell morphology, growth characteristics and metabolic activity (Matas et al 1976;Sutherland et al 1977;Russell, 1985). In studies of chondrocytes subjected to hydrodynamic forces cell proliferation rates are approximately 50 % greater and the extracellular matrix is improved (Gupta et al 1991;Balis et al 1999).…”

Section: Principles Of Tissue Engineeringmentioning

confidence: 99%

Tissue engineering of the gastrointestinal tract for surgical replacement: a nutrition tool of the future?

Grikscheit

2003

Proc. Nutr. Soc.

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Optimal nutrition depends on the multiple complex functions performed by the gastrointestinal tract, which range from basic functions such as storage, conduit and mechanical processing to more finely regulated capabilities such as vectorial transport, immune defence and cell signalling. Surgical strategies to supply lacking gastrointestinal tract tissues have relied on either replacement by proxy (surgical substitution) or the introduction of prostheses. Tissue engineering seeks to replace missing tissues with engineered tissues that more accurately reproduce the native physiological and anatomical milieu. It is now possible to engineer several areas of the gastrointestinal tract with high fidelity, and to employ tissue-engineered bowel in replacement in animal models. These replacement models have reflected excellent anatomical and physiological recapitulation of native bowel by the tissue-engineered constructsin vivo.

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Hepatocellular Transplantation for Metabolic Deficiencies: Decrease of Plasma Bilirubin in Gunn Rats

Cited by 286 publications

References 17 publications

Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats.

Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats.

Stem cell therapy for inherited metabolic disorders of the liver

Tissue engineering of the gastrointestinal tract for surgical replacement: a nutrition tool of the future?

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