Efficient Generation of Hepatoblasts From Human ES Cells and iPS Cells by Transient Overexpression of Homeobox Gene HEX
Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver...
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| Veröffentlicht in: | Molecular therapy 2011-02, Vol.19 (2), p.400-407 |
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| creator | Inamura, Mitsuru Kawabata, Kenji Takayama, Kazuo Tashiro, Katsuhisa Sakurai, Fuminori Katayama, Kazufumi Toyoda, Masashi Akutsu, Hidenori Miyagawa, Yoshitaka Okita, Hajime Kiyokawa, Nobutaka Umezawa, Akihiro Hayakawa, Takao Furue, Miho K Mizuguchi, Hiroyuki |
| description | Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications. |
| doi_str_mv | 10.1038/mt.2010.241 |
| format | Article |
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Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2010.241</identifier><identifier>PMID: 21102561</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenoviridae - genetics ; Adenovirus ; Biochemistry ; Biomedical research ; Cell Differentiation - genetics ; Cell Differentiation - physiology ; Childrens health ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - metabolism ; Drug dosages ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - metabolism ; Genes ; Genes, Homeobox - genetics ; Genes, Homeobox - physiology ; Genetic Vectors - genetics ; Growth factors ; Hepatocytes - cytology ; Homeodomain Proteins - genetics ; Homeodomain Proteins - physiology ; Humans ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Liver ; Molecular biology ; Original ; Pharmaceutical sciences ; Proteins ; R&D ; Research & development ; Stem cells ; Transcription Factors - genetics ; Transcription Factors - physiology</subject><ispartof>Molecular therapy, 2011-02, Vol.19 (2), p.400-407</ispartof><rights>2011 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Feb 2011</rights><rights>Copyright © 2011 The American Society of Gene & Cell Therapy 2011 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-b0726f6e6fa7e10e0af38e2dce63e1e8b843a7ba4a728632a9b5faa60fe7b94f3</citedby><cites>FETCH-LOGICAL-c553t-b0726f6e6fa7e10e0af38e2dce63e1e8b843a7ba4a728632a9b5faa60fe7b94f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034848/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1791985415?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21102561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inamura, Mitsuru</creatorcontrib><creatorcontrib>Kawabata, Kenji</creatorcontrib><creatorcontrib>Takayama, Kazuo</creatorcontrib><creatorcontrib>Tashiro, Katsuhisa</creatorcontrib><creatorcontrib>Sakurai, Fuminori</creatorcontrib><creatorcontrib>Katayama, Kazufumi</creatorcontrib><creatorcontrib>Toyoda, Masashi</creatorcontrib><creatorcontrib>Akutsu, Hidenori</creatorcontrib><creatorcontrib>Miyagawa, Yoshitaka</creatorcontrib><creatorcontrib>Okita, Hajime</creatorcontrib><creatorcontrib>Kiyokawa, Nobutaka</creatorcontrib><creatorcontrib>Umezawa, Akihiro</creatorcontrib><creatorcontrib>Hayakawa, Takao</creatorcontrib><creatorcontrib>Furue, Miho K</creatorcontrib><creatorcontrib>Mizuguchi, Hiroyuki</creatorcontrib><title>Efficient Generation of Hepatoblasts From Human ES Cells and iPS Cells by Transient Overexpression of Homeobox Gene HEX</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.</description><subject>Adenoviridae - genetics</subject><subject>Adenovirus</subject><subject>Biochemistry</subject><subject>Biomedical research</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - physiology</subject><subject>Childrens health</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug dosages</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Genes</subject><subject>Genes, Homeobox - genetics</subject><subject>Genes, Homeobox - physiology</subject><subject>Genetic Vectors - genetics</subject><subject>Growth factors</subject><subject>Hepatocytes - cytology</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - physiology</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Liver</subject><subject>Molecular biology</subject><subject>Original</subject><subject>Pharmaceutical sciences</subject><subject>Proteins</subject><subject>R&D</subject><subject>Research & development</subject><subject>Stem cells</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - physiology</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</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>eNp9kd9rFDEQx4MotlaffJeADwpyNb83-1KQ49oTChWs4FvI7k00ZTc5k-zZ_vfmer1DRXwIM8N88k1mvgi9pOSUEq7fj-WUkVowQR-hYyqZnBHCxONDTtURepbzTc2obNVTdMQoJUwqeox-LpzzvYdQ8AUESLb4GHB0eAlrW2I32FwyPk9xxMtptAEvPuM5DEPGNqyw_7Svujt8nWzI90pXG0hwu06Q814tjhC7eHv_CF4uvj5HT5wdMrx4iCfoy_nier6cXV5dfJx_uJz1UvIy60jDlFOgnG2AEiDWcQ1s1YPiQEF3WnDbdFbYhmnFmW076axVxEHTtcLxE3S2011P3Qj1XijJDmad_GjTnYnWmz87wX833-LGcMKFFroKvHkQSPHHBLmY0ee-zmwDxCkbLVrBOWWqkm__S1KlNKtH0oq-_gu9iVMKdRGGNi1ttRRUVurdjupTzDmBO3ybErO13ozFbK031fpKv_p90gO797oCcgdA3ffGQzJ5a3wPK5-gL2YV_T-FfwHMDbwz</recordid><startdate>20110201</startdate><enddate>20110201</enddate><creator>Inamura, Mitsuru</creator><creator>Kawabata, Kenji</creator><creator>Takayama, Kazuo</creator><creator>Tashiro, Katsuhisa</creator><creator>Sakurai, Fuminori</creator><creator>Katayama, Kazufumi</creator><creator>Toyoda, Masashi</creator><creator>Akutsu, Hidenori</creator><creator>Miyagawa, Yoshitaka</creator><creator>Okita, Hajime</creator><creator>Kiyokawa, Nobutaka</creator><creator>Umezawa, Akihiro</creator><creator>Hayakawa, Takao</creator><creator>Furue, Miho K</creator><creator>Mizuguchi, Hiroyuki</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>6I.</scope><scope>AAFTH</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>7X7</scope><scope>7XB</scope><scope>88E</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>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110201</creationdate><title>Efficient Generation of Hepatoblasts From Human ES Cells and iPS Cells by Transient Overexpression of Homeobox Gene HEX</title><author>Inamura, Mitsuru ; Kawabata, Kenji ; Takayama, Kazuo ; Tashiro, Katsuhisa ; Sakurai, Fuminori ; Katayama, Kazufumi ; Toyoda, Masashi ; Akutsu, Hidenori ; Miyagawa, Yoshitaka ; Okita, Hajime ; Kiyokawa, Nobutaka ; Umezawa, Akihiro ; Hayakawa, Takao ; Furue, Miho K ; Mizuguchi, Hiroyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c553t-b0726f6e6fa7e10e0af38e2dce63e1e8b843a7ba4a728632a9b5faa60fe7b94f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenoviridae - 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genetics</topic><topic>Transcription Factors - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inamura, Mitsuru</creatorcontrib><creatorcontrib>Kawabata, Kenji</creatorcontrib><creatorcontrib>Takayama, Kazuo</creatorcontrib><creatorcontrib>Tashiro, Katsuhisa</creatorcontrib><creatorcontrib>Sakurai, Fuminori</creatorcontrib><creatorcontrib>Katayama, Kazufumi</creatorcontrib><creatorcontrib>Toyoda, Masashi</creatorcontrib><creatorcontrib>Akutsu, Hidenori</creatorcontrib><creatorcontrib>Miyagawa, Yoshitaka</creatorcontrib><creatorcontrib>Okita, Hajime</creatorcontrib><creatorcontrib>Kiyokawa, Nobutaka</creatorcontrib><creatorcontrib>Umezawa, Akihiro</creatorcontrib><creatorcontrib>Hayakawa, Takao</creatorcontrib><creatorcontrib>Furue, Miho K</creatorcontrib><creatorcontrib>Mizuguchi, Hiroyuki</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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 Edition)</collection><collection>ProQuest Central UK/Ireland</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>Medical Database</collection><collection>Biological Science 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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inamura, Mitsuru</au><au>Kawabata, Kenji</au><au>Takayama, Kazuo</au><au>Tashiro, Katsuhisa</au><au>Sakurai, Fuminori</au><au>Katayama, Kazufumi</au><au>Toyoda, Masashi</au><au>Akutsu, Hidenori</au><au>Miyagawa, Yoshitaka</au><au>Okita, Hajime</au><au>Kiyokawa, Nobutaka</au><au>Umezawa, Akihiro</au><au>Hayakawa, Takao</au><au>Furue, Miho K</au><au>Mizuguchi, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficient Generation of Hepatoblasts From Human ES Cells and iPS Cells by Transient Overexpression of Homeobox Gene HEX</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2011-02-01</date><risdate>2011</risdate><volume>19</volume><issue>2</issue><spage>400</spage><epage>407</epage><pages>400-407</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21102561</pmid><doi>10.1038/mt.2010.241</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; PubMed Central; Alma/SFX Local Collection |
| subjects | Adenoviridae - genetics Adenovirus Biochemistry Biomedical research Cell Differentiation - genetics Cell Differentiation - physiology Childrens health Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Drug dosages Embryonic Stem Cells - cytology Embryonic Stem Cells - metabolism Genes Genes, Homeobox - genetics Genes, Homeobox - physiology Genetic Vectors - genetics Growth factors Hepatocytes - cytology Homeodomain Proteins - genetics Homeodomain Proteins - physiology Humans Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Liver Molecular biology Original Pharmaceutical sciences Proteins R&D Research & development Stem cells Transcription Factors - genetics Transcription Factors - physiology |
| title | Efficient Generation of Hepatoblasts From Human ES Cells and iPS Cells by Transient Overexpression of Homeobox Gene HEX |
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