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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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. |
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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. 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.</description><identifier>ISSN: 0939-4451</identifier><identifier>EISSN: 1438-2199</identifier><identifier>DOI: 10.1007/s00726-013-1594-x</identifier><identifier>PMID: 24081877</identifier><language>eng</language><publisher>Vienna: Springer-Verlag</publisher><subject>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</subject><ispartof>Amino acids, 2013-12, Vol.45 (6), p.1343-1351</ispartof><rights>Springer-Verlag Wien 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c506t-2ed099489b608d8dc5602966fa2e43f6e1928043df1432cefcaa332c4d68e9823</citedby><cites>FETCH-LOGICAL-c506t-2ed099489b608d8dc5602966fa2e43f6e1928043df1432cefcaa332c4d68e9823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00726-013-1594-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00726-013-1594-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24081877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tamai, Miho</creatorcontrib><creatorcontrib>Aoki, Mami</creatorcontrib><creatorcontrib>Nishimura, Akihito</creatorcontrib><creatorcontrib>Morishita, Koji</creatorcontrib><creatorcontrib>Tagawa, Yoh-ichi</creatorcontrib><title>In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model</title><title>Amino acids</title><addtitle>Amino Acids</addtitle><addtitle>Amino Acids</addtitle><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.</description><subject>ammonia</subject><subject>Analytical Chemistry</subject><subject>Animals</subject><subject>bile</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>cell death</subject><subject>drug toxicity</subject><subject>embryonic stem cells</subject><subject>Embryonic Stem Cells - cytology</subject><subject>functional properties</subject><subject>hepatocytes</subject><subject>In Vitro Techniques</subject><subject>Life Sciences</subject><subject>liver</subject><subject>Liver - cytology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>metabolites</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Animal</subject><subject>Neurobiology</subject><subject>Original Article</subject><subject>Ornithine - metabolism</subject><subject>physiology</subject><subject>Proteomics</subject><subject>urea</subject><subject>Urea - metabolism</subject><issn>0939-4451</issn><issn>1438-2199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kEFPHSEUhYlpo6_qD-hGSbqmXhiGB8vG2NbExIV1TXhw5xUzMzxhxvj-vZhR01VZXO4N55wbPkK-cvjOAdYXpRahGPCG8dZI9nxAVlw2mgluzCeyAtMYJmXLj8iXUh4AuNBcHZIjIUFzvV6vyPZ6pE9xyolm9G4Xp7l3U0wjTR2d_iKdMzrq976vbYnjlg5zjiNSHDZ5n8boaZlwoB77ngXM8QkDje-RfR0zHVLA_oR87lxf8PTtPib3P6_-XP5mN7e_ri9_3DDfgpqYwADGSG02CnTQwbcKhFGqcwJl0ynkRmiQTejqP4XHzjvX1EYGpdFo0RyTb0vuLqfHGctkH9Kcx7rScqlAghKtqSq-qHxOpWTs7C7HweW95WBf0doFra1o7Sta-1w9Z2_J82bA8OF4Z1kFYhGU-jRuMf-z-j-p54upc8m6bY7F3t8J4ArqUWslmxeLUI4i</recordid><startdate>20131201</startdate><enddate>20131201</enddate><creator>Tamai, Miho</creator><creator>Aoki, Mami</creator><creator>Nishimura, Akihito</creator><creator>Morishita, Koji</creator><creator>Tagawa, Yoh-ichi</creator><general>Springer-Verlag</general><general>Springer Vienna</general><general>Springer Nature B.V</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20131201</creationdate><title>In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model</title><author>Tamai, Miho ; Aoki, Mami ; Nishimura, Akihito ; Morishita, Koji ; Tagawa, Yoh-ichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-2ed099489b608d8dc5602966fa2e43f6e1928043df1432cefcaa332c4d68e9823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>ammonia</topic><topic>Analytical Chemistry</topic><topic>Animals</topic><topic>bile</topic><topic>Biochemical Engineering</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>cell death</topic><topic>drug toxicity</topic><topic>embryonic stem cells</topic><topic>Embryonic Stem Cells - cytology</topic><topic>functional properties</topic><topic>hepatocytes</topic><topic>In Vitro Techniques</topic><topic>Life Sciences</topic><topic>liver</topic><topic>Liver - cytology</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>metabolites</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Animal</topic><topic>Neurobiology</topic><topic>Original Article</topic><topic>Ornithine - metabolism</topic><topic>physiology</topic><topic>Proteomics</topic><topic>urea</topic><topic>Urea - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tamai, Miho</creatorcontrib><creatorcontrib>Aoki, Mami</creatorcontrib><creatorcontrib>Nishimura, Akihito</creatorcontrib><creatorcontrib>Morishita, Koji</creatorcontrib><creatorcontrib>Tagawa, Yoh-ichi</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Amino acids</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tamai, Miho</au><au>Aoki, Mami</au><au>Nishimura, Akihito</au><au>Morishita, Koji</au><au>Tagawa, Yoh-ichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model</atitle><jtitle>Amino acids</jtitle><stitle>Amino Acids</stitle><addtitle>Amino Acids</addtitle><date>2013-12-01</date><risdate>2013</risdate><volume>45</volume><issue>6</issue><spage>1343</spage><epage>1351</epage><pages>1343-1351</pages><issn>0939-4451</issn><eissn>1438-2199</eissn><abstract>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.</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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