Loading…
Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells
Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharm...
Saved in:
| Published in: | Stem cells translational medicine 2013-07, Vol.2 (7), p.505-509 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3 |
| container_end_page | 509 |
| container_issue | 7 |
| container_start_page | 505 |
| container_title | Stem cells translational medicine |
| container_volume | 2 |
| creator | Medine, Claire N. Lucendo-Villarin, Baltasar Storck, Christopher Wang, Faye Szkolnicka, Dagmara Khan, Ferdous Pernagallo, Salvatore Black, James R. Marriage, Howard M. Ross, James A. Bradley, Mark Iredale, John P. Flint, Oliver Hay, David C. |
| description | Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharmacological compounds. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, this approach was capable of modeling metabolic differences observed in the population. These studies provide robust hepatocyte models which will likely contribute to improvements in drug safety testing.
Faithfully recapitulating human physiology “in a dish” from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue‐specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom‐built and well‐defined compound set and compared with primary human hepatocytes. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell‐derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field. |
| doi_str_mv | 10.5966/sctm.2012-0138 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3697818</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2290012674</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3</originalsourceid><addsrcrecordid>eNqFUU1LAzEQDaKoqFePsuB5az42yeYiSLVWqChUzyGbzdbIbrMmW7U3f4K_0V9iltaiJ8NAZpI3bx7zADhGcEAFY2dBd80AQ4RTiEi-BfYxojxlNIfbm5xle-AohGcYDxNMYLgL9jDhlFOY7YPJpXk1tWvtfJaM7ezp6-NzZEtT226ZjE2rOte5d6v78tbF95CMvGuS-3rhbes6M--SaWeaZGjqOhyCnUrVwRyt7wPwOLp6GI7Tyd31zfBikmpKMpoaTlhVGVVUKjcshwrmpWCQF6gURGWa5UpQrlAMaDSpWIEY10VJRIEFLTU5AOcr3nZRNKbUUYVXtWy9bZRfSqes_Pszt09y5l4lYYLnKI8Ep2sC714WJnTy2S38PGqWGAsYN8p4FlGDFUp7F4I31WYCgrI3QPYGyN4A2RsQG05-69rAf9YdAWIFeLO1Wf5DJ6fDBxIrgmMvJd_Y-ZWN</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2290012674</pqid></control><display><type>article</type><title>Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells</title><source>Publicly Available Content Database</source><source>PubMed Central</source><creator>Medine, Claire N. ; Lucendo-Villarin, Baltasar ; Storck, Christopher ; Wang, Faye ; Szkolnicka, Dagmara ; Khan, Ferdous ; Pernagallo, Salvatore ; Black, James R. ; Marriage, Howard M. ; Ross, James A. ; Bradley, Mark ; Iredale, John P. ; Flint, Oliver ; Hay, David C.</creator><creatorcontrib>Medine, Claire N. ; Lucendo-Villarin, Baltasar ; Storck, Christopher ; Wang, Faye ; Szkolnicka, Dagmara ; Khan, Ferdous ; Pernagallo, Salvatore ; Black, James R. ; Marriage, Howard M. ; Ross, James A. ; Bradley, Mark ; Iredale, John P. ; Flint, Oliver ; Hay, David C.</creatorcontrib><description>Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharmacological compounds. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, this approach was capable of modeling metabolic differences observed in the population. These studies provide robust hepatocyte models which will likely contribute to improvements in drug safety testing.
Faithfully recapitulating human physiology “in a dish” from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue‐specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom‐built and well‐defined compound set and compared with primary human hepatocytes. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell‐derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field.</description><identifier>ISSN: 2157-6564</identifier><identifier>EISSN: 2157-6580</identifier><identifier>DOI: 10.5966/sctm.2012-0138</identifier><identifier>PMID: 23757504</identifier><language>eng</language><publisher>United States: AlphaMed Press</publisher><subject>Cell culture ; Cell differentiation ; Cell Line, Transformed ; Cell surface ; Cell Survival - drug effects ; Cell Survival - physiology ; Cell-Based Drug Development, Screening, and Toxicology ; Chemical and Drug Induced Liver Injury - pathology ; Chemical and Drug Induced Liver Injury - physiopathology ; Councils ; Cytochrome ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Data analysis ; Embryonic stem cells ; Employment ; Enzymes ; Gene expression ; Gene Expression Regulation, Enzymologic - drug effects ; Gene Expression Regulation, Enzymologic - physiology ; Hepatocyte differentiation ; Hepatocytes ; Hepatocytes - cytology ; Hepatocytes - drug effects ; Hepatocytes - physiology ; Hepatotoxicity ; Humans ; iPS ; Liver ; Medical research ; Metabolism ; Metabolites ; Nonsteroidal anti-inflammatory drugs ; Pharmacovigilance ; Pluripotency ; Pluripotent Stem Cells - cytology ; Pluripotent Stem Cells - drug effects ; Pluripotent Stem Cells - physiology ; Population studies ; Primary Cell Culture ; Proteins ; Reference Standards ; Reproducibility of Results ; Stem cell ; Stem cells ; Stock options ; Toxicity ; Toxicity Tests - methods ; Toxicity Tests - standards</subject><ispartof>Stem cells translational medicine, 2013-07, Vol.2 (7), p.505-509</ispartof><rights>2013 AlphaMed Press</rights><rights>2013. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>AlphaMed Press 1066-5099/2013/$20.00/0 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3</citedby><cites>FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2290012674/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2290012674?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23757504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Medine, Claire N.</creatorcontrib><creatorcontrib>Lucendo-Villarin, Baltasar</creatorcontrib><creatorcontrib>Storck, Christopher</creatorcontrib><creatorcontrib>Wang, Faye</creatorcontrib><creatorcontrib>Szkolnicka, Dagmara</creatorcontrib><creatorcontrib>Khan, Ferdous</creatorcontrib><creatorcontrib>Pernagallo, Salvatore</creatorcontrib><creatorcontrib>Black, James R.</creatorcontrib><creatorcontrib>Marriage, Howard M.</creatorcontrib><creatorcontrib>Ross, James A.</creatorcontrib><creatorcontrib>Bradley, Mark</creatorcontrib><creatorcontrib>Iredale, John P.</creatorcontrib><creatorcontrib>Flint, Oliver</creatorcontrib><creatorcontrib>Hay, David C.</creatorcontrib><title>Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells</title><title>Stem cells translational medicine</title><addtitle>Stem Cells Transl Med</addtitle><description>Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharmacological compounds. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, this approach was capable of modeling metabolic differences observed in the population. These studies provide robust hepatocyte models which will likely contribute to improvements in drug safety testing.
Faithfully recapitulating human physiology “in a dish” from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue‐specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom‐built and well‐defined compound set and compared with primary human hepatocytes. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell‐derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field.</description><subject>Cell culture</subject><subject>Cell differentiation</subject><subject>Cell Line, Transformed</subject><subject>Cell surface</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - physiology</subject><subject>Cell-Based Drug Development, Screening, and Toxicology</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>Chemical and Drug Induced Liver Injury - physiopathology</subject><subject>Councils</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Data analysis</subject><subject>Embryonic stem cells</subject><subject>Employment</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Gene Expression Regulation, Enzymologic - physiology</subject><subject>Hepatocyte differentiation</subject><subject>Hepatocytes</subject><subject>Hepatocytes - cytology</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - physiology</subject><subject>Hepatotoxicity</subject><subject>Humans</subject><subject>iPS</subject><subject>Liver</subject><subject>Medical research</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Pharmacovigilance</subject><subject>Pluripotency</subject><subject>Pluripotent Stem Cells - cytology</subject><subject>Pluripotent Stem Cells - drug effects</subject><subject>Pluripotent Stem Cells - physiology</subject><subject>Population studies</subject><subject>Primary Cell Culture</subject><subject>Proteins</subject><subject>Reference Standards</subject><subject>Reproducibility of Results</subject><subject>Stem cell</subject><subject>Stem cells</subject><subject>Stock options</subject><subject>Toxicity</subject><subject>Toxicity Tests - methods</subject><subject>Toxicity Tests - standards</subject><issn>2157-6564</issn><issn>2157-6580</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNqFUU1LAzEQDaKoqFePsuB5az42yeYiSLVWqChUzyGbzdbIbrMmW7U3f4K_0V9iltaiJ8NAZpI3bx7zADhGcEAFY2dBd80AQ4RTiEi-BfYxojxlNIfbm5xle-AohGcYDxNMYLgL9jDhlFOY7YPJpXk1tWvtfJaM7ezp6-NzZEtT226ZjE2rOte5d6v78tbF95CMvGuS-3rhbes6M--SaWeaZGjqOhyCnUrVwRyt7wPwOLp6GI7Tyd31zfBikmpKMpoaTlhVGVVUKjcshwrmpWCQF6gURGWa5UpQrlAMaDSpWIEY10VJRIEFLTU5AOcr3nZRNKbUUYVXtWy9bZRfSqes_Pszt09y5l4lYYLnKI8Ep2sC714WJnTy2S38PGqWGAsYN8p4FlGDFUp7F4I31WYCgrI3QPYGyN4A2RsQG05-69rAf9YdAWIFeLO1Wf5DJ6fDBxIrgmMvJd_Y-ZWN</recordid><startdate>201307</startdate><enddate>201307</enddate><creator>Medine, Claire N.</creator><creator>Lucendo-Villarin, Baltasar</creator><creator>Storck, Christopher</creator><creator>Wang, Faye</creator><creator>Szkolnicka, Dagmara</creator><creator>Khan, Ferdous</creator><creator>Pernagallo, Salvatore</creator><creator>Black, James R.</creator><creator>Marriage, Howard M.</creator><creator>Ross, James A.</creator><creator>Bradley, Mark</creator><creator>Iredale, John P.</creator><creator>Flint, Oliver</creator><creator>Hay, David C.</creator><general>AlphaMed Press</general><general>Oxford University Press</general><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>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>201307</creationdate><title>Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells</title><author>Medine, Claire N. ; Lucendo-Villarin, Baltasar ; Storck, Christopher ; Wang, Faye ; Szkolnicka, Dagmara ; Khan, Ferdous ; Pernagallo, Salvatore ; Black, James R. ; Marriage, Howard M. ; Ross, James A. ; Bradley, Mark ; Iredale, John P. ; Flint, Oliver ; Hay, David C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Cell culture</topic><topic>Cell differentiation</topic><topic>Cell Line, Transformed</topic><topic>Cell surface</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - physiology</topic><topic>Cell-Based Drug Development, Screening, and Toxicology</topic><topic>Chemical and Drug Induced Liver Injury - pathology</topic><topic>Chemical and Drug Induced Liver Injury - physiopathology</topic><topic>Councils</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Data analysis</topic><topic>Embryonic stem cells</topic><topic>Employment</topic><topic>Enzymes</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>Gene Expression Regulation, Enzymologic - physiology</topic><topic>Hepatocyte differentiation</topic><topic>Hepatocytes</topic><topic>Hepatocytes - cytology</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - physiology</topic><topic>Hepatotoxicity</topic><topic>Humans</topic><topic>iPS</topic><topic>Liver</topic><topic>Medical research</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Nonsteroidal anti-inflammatory drugs</topic><topic>Pharmacovigilance</topic><topic>Pluripotency</topic><topic>Pluripotent Stem Cells - cytology</topic><topic>Pluripotent Stem Cells - drug effects</topic><topic>Pluripotent Stem Cells - physiology</topic><topic>Population studies</topic><topic>Primary Cell Culture</topic><topic>Proteins</topic><topic>Reference Standards</topic><topic>Reproducibility of Results</topic><topic>Stem cell</topic><topic>Stem cells</topic><topic>Stock options</topic><topic>Toxicity</topic><topic>Toxicity Tests - methods</topic><topic>Toxicity Tests - standards</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Medine, Claire N.</creatorcontrib><creatorcontrib>Lucendo-Villarin, Baltasar</creatorcontrib><creatorcontrib>Storck, Christopher</creatorcontrib><creatorcontrib>Wang, Faye</creatorcontrib><creatorcontrib>Szkolnicka, Dagmara</creatorcontrib><creatorcontrib>Khan, Ferdous</creatorcontrib><creatorcontrib>Pernagallo, Salvatore</creatorcontrib><creatorcontrib>Black, James R.</creatorcontrib><creatorcontrib>Marriage, Howard M.</creatorcontrib><creatorcontrib>Ross, James A.</creatorcontrib><creatorcontrib>Bradley, Mark</creatorcontrib><creatorcontrib>Iredale, John P.</creatorcontrib><creatorcontrib>Flint, Oliver</creatorcontrib><creatorcontrib>Hay, David C.</creatorcontrib><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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</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>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Stem cells translational medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Medine, Claire N.</au><au>Lucendo-Villarin, Baltasar</au><au>Storck, Christopher</au><au>Wang, Faye</au><au>Szkolnicka, Dagmara</au><au>Khan, Ferdous</au><au>Pernagallo, Salvatore</au><au>Black, James R.</au><au>Marriage, Howard M.</au><au>Ross, James A.</au><au>Bradley, Mark</au><au>Iredale, John P.</au><au>Flint, Oliver</au><au>Hay, David C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells</atitle><jtitle>Stem cells translational medicine</jtitle><addtitle>Stem Cells Transl Med</addtitle><date>2013-07</date><risdate>2013</risdate><volume>2</volume><issue>7</issue><spage>505</spage><epage>509</epage><pages>505-509</pages><issn>2157-6564</issn><eissn>2157-6580</eissn><abstract>Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharmacological compounds. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, this approach was capable of modeling metabolic differences observed in the population. These studies provide robust hepatocyte models which will likely contribute to improvements in drug safety testing.
Faithfully recapitulating human physiology “in a dish” from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue‐specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom‐built and well‐defined compound set and compared with primary human hepatocytes. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell‐derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field.</abstract><cop>United States</cop><pub>AlphaMed Press</pub><pmid>23757504</pmid><doi>10.5966/sctm.2012-0138</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2157-6564 |
| ispartof | Stem cells translational medicine, 2013-07, Vol.2 (7), p.505-509 |
| issn | 2157-6564 2157-6580 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3697818 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Cell culture Cell differentiation Cell Line, Transformed Cell surface Cell Survival - drug effects Cell Survival - physiology Cell-Based Drug Development, Screening, and Toxicology Chemical and Drug Induced Liver Injury - pathology Chemical and Drug Induced Liver Injury - physiopathology Councils Cytochrome Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Data analysis Embryonic stem cells Employment Enzymes Gene expression Gene Expression Regulation, Enzymologic - drug effects Gene Expression Regulation, Enzymologic - physiology Hepatocyte differentiation Hepatocytes Hepatocytes - cytology Hepatocytes - drug effects Hepatocytes - physiology Hepatotoxicity Humans iPS Liver Medical research Metabolism Metabolites Nonsteroidal anti-inflammatory drugs Pharmacovigilance Pluripotency Pluripotent Stem Cells - cytology Pluripotent Stem Cells - drug effects Pluripotent Stem Cells - physiology Population studies Primary Cell Culture Proteins Reference Standards Reproducibility of Results Stem cell Stem cells Stock options Toxicity Toxicity Tests - methods Toxicity Tests - standards |
| title | Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T06%3A26%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Developing%20High%E2%80%90Fidelity%20Hepatotoxicity%20Models%20From%20Pluripotent%20Stem%20Cells&rft.jtitle=Stem%20cells%20translational%20medicine&rft.au=Medine,%20Claire%20N.&rft.date=2013-07&rft.volume=2&rft.issue=7&rft.spage=505&rft.epage=509&rft.pages=505-509&rft.issn=2157-6564&rft.eissn=2157-6580&rft_id=info:doi/10.5966/sctm.2012-0138&rft_dat=%3Cproquest_pubme%3E2290012674%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c5345-e736ffeabfa8e680a08d9607b1d93a4c68a957a17a10ec3f6b167cbd39b295dc3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2290012674&rft_id=info:pmid/23757504&rfr_iscdi=true |