In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model

Ammonia, a toxic metabolite, is converted to urea in hepatocytes via the urea cycle, a process necessary for cell/organismal survival. In liver, hepatocytes, polygonal and multipolar structures, have a few sides which face hepatic sinusoids and adjacent hepatocytes to form intercellular bile canalic...

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Veröffentlicht in:Amino acids 2013-12, Vol.45 (6), p.1343-1351
Hauptverfasser: Tamai, Miho, Aoki, Mami, Nishimura, Akihito, Morishita, Koji, Tagawa, Yoh-ichi
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container_end_page 1351
container_issue 6
container_start_page 1343
container_title Amino acids
container_volume 45
creator Tamai, Miho
Aoki, Mami
Nishimura, Akihito
Morishita, Koji
Tagawa, Yoh-ichi
description Ammonia, a toxic metabolite, is converted to urea in hepatocytes via the urea cycle, a process necessary for cell/organismal survival. In liver, hepatocytes, polygonal and multipolar structures, have a few sides which face hepatic sinusoids and adjacent hepatocytes to form intercellular bile canaliculi connecting to the ductules. The critical nature of this three-dimensional environment should be related to the maintenance of hepatocyte function such as urea synthesis. Recently, we established an in vitro liver model derived from murine embryonic stem cells, IVLᵐᴱS, which included the hepatocyte layer and a surrounding sinusoid vascular-like network. The IVLᵐᴱSculture, where the hepatocyte is polarized in a similar fashion to its in vivo counterpart, could successfully recapitulate in vivo results. L-Ornithine is an intermediate of the urea cycle, but supplemental L-ornithine does not activate the urea cycle in the apolar primary hepatocyte of monolayer culture. In the IVLᵐᴱS, supplemental L-ornithine could activate the urea cycle, and also protect against ammonium/alcohol-induced hepatocyte death. While the IVLᵐᴱSdisplays architectural and functional properties similar to the liver, primary hepatocyte of monolayer culture fail to model critical functional aspects of liver physiology. We propose that the IVLᵐᴱSwill represent a useful, humane alternative to animal studies for drug toxicity and mechanistic studies of liver injury.
doi_str_mv 10.1007/s00726-013-1594-x
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In liver, hepatocytes, polygonal and multipolar structures, have a few sides which face hepatic sinusoids and adjacent hepatocytes to form intercellular bile canaliculi connecting to the ductules. The critical nature of this three-dimensional environment should be related to the maintenance of hepatocyte function such as urea synthesis. Recently, we established an in vitro liver model derived from murine embryonic stem cells, IVLᵐᴱS, which included the hepatocyte layer and a surrounding sinusoid vascular-like network. The IVLᵐᴱSculture, where the hepatocyte is polarized in a similar fashion to its in vivo counterpart, could successfully recapitulate in vivo results. L-Ornithine is an intermediate of the urea cycle, but supplemental L-ornithine does not activate the urea cycle in the apolar primary hepatocyte of monolayer culture. In the IVLᵐᴱS, supplemental L-ornithine could activate the urea cycle, and also protect against ammonium/alcohol-induced hepatocyte death. 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While the IVLᵐᴱSdisplays architectural and functional properties similar to the liver, primary hepatocyte of monolayer culture fail to model critical functional aspects of liver physiology. We propose that the IVLᵐᴱSwill represent a useful, humane alternative to animal studies for drug toxicity and mechanistic studies of liver injury.</abstract><cop>Vienna</cop><pub>Springer-Verlag</pub><pmid>24081877</pmid><doi>10.1007/s00726-013-1594-x</doi><tpages>9</tpages></addata></record>
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subjects ammonia
Analytical Chemistry
Animals
bile
Biochemical Engineering
Biochemistry
Biomedical and Life Sciences
cell death
drug toxicity
embryonic stem cells
Embryonic Stem Cells - cytology
functional properties
hepatocytes
In Vitro Techniques
Life Sciences
liver
Liver - cytology
Liver - metabolism
Male
metabolites
Mice
Mice, Inbred BALB C
Models, Animal
Neurobiology
Original Article
Ornithine - metabolism
physiology
Proteomics
urea
Urea - metabolism
title In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model
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