Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells

Objective: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors—NKx2 homeobox 1 ( NKx2-1 , formerly called TTF-1 ) and Paired box gene 8 ( Pa...

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Veröffentlicht in:Thyroid (New York, N.Y.) N.Y.), 2013-04, Vol.23 (4), p.385-391
Hauptverfasser: Ma, Risheng, Latif, Rauf, Davies, Terry F.
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creator Ma, Risheng
Latif, Rauf
Davies, Terry F.
description Objective: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors—NKx2 homeobox 1 ( NKx2-1 , formerly called TTF-1 ) and Paired box gene 8 ( Pax8 )—are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter ( NIS ), thyrotropin (TSH) receptor ( TSHR ), thyroglobulin ( Tg ), and thyroid peroxidase ( TPO ) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. Methods: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS , TSHR , Tg , and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. Results: The four thyroid-specific genes NIS , TSHR , Tg , and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR , Tg , and TPO genes was detected in cells expressing just NKx2-1 , and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS , TSHR , Tg , and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1 . Conclusion: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures.
doi_str_mv 10.1089/thy.2012.0644
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The thyroid transcription factors—NKx2 homeobox 1 ( NKx2-1 , formerly called TTF-1 ) and Paired box gene 8 ( Pax8 )—are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter ( NIS ), thyrotropin (TSH) receptor ( TSHR ), thyroglobulin ( Tg ), and thyroid peroxidase ( TPO ) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. Methods: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS , TSHR , Tg , and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. Results: The four thyroid-specific genes NIS , TSHR , Tg , and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR , Tg , and TPO genes was detected in cells expressing just NKx2-1 , and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS , TSHR , Tg , and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1 . Conclusion: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures.</description><identifier>ISSN: 1050-7256</identifier><identifier>EISSN: 1557-9077</identifier><identifier>DOI: 10.1089/thy.2012.0644</identifier><identifier>PMID: 23360087</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Animals ; Cell Differentiation ; Endoderm - cytology ; Endoderm - metabolism ; Iodide Peroxidase - genetics ; Iodide Peroxidase - metabolism ; Mice ; Multipotent Stem Cells - cytology ; Multipotent Stem Cells - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Paired Box Transcription Factors - genetics ; Paired Box Transcription Factors - metabolism ; PAX8 Transcription Factor ; Receptors, Thyrotropin - genetics ; Receptors, Thyrotropin - metabolism ; Special ; Special Article ; Symporters - genetics ; Symporters - metabolism ; Thyroglobulin - genetics ; Thyroglobulin - metabolism ; Thyroid Gland - cytology ; Thyroid Gland - metabolism ; Thyroid Nuclear Factor 1 ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Thyroid (New York, N.Y.), 2013-04, Vol.23 (4), p.385-391</ispartof><rights>2013, Mary Ann Liebert, Inc.</rights><rights>Copyright 2013, Mary Ann Liebert, Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-de9cc3a0e6502764d8be9eba2cb2e3e5ab5a891fced9c17e5e5edf574bf9df8b3</citedby><cites>FETCH-LOGICAL-c497t-de9cc3a0e6502764d8be9eba2cb2e3e5ab5a891fced9c17e5e5edf574bf9df8b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23360087$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Risheng</creatorcontrib><creatorcontrib>Latif, Rauf</creatorcontrib><creatorcontrib>Davies, Terry F.</creatorcontrib><title>Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells</title><title>Thyroid (New York, N.Y.)</title><addtitle>Thyroid</addtitle><description>Objective: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors—NKx2 homeobox 1 ( NKx2-1 , formerly called TTF-1 ) and Paired box gene 8 ( Pax8 )—are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter ( NIS ), thyrotropin (TSH) receptor ( TSHR ), thyroglobulin ( Tg ), and thyroid peroxidase ( TPO ) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. Methods: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS , TSHR , Tg , and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. Results: The four thyroid-specific genes NIS , TSHR , Tg , and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR , Tg , and TPO genes was detected in cells expressing just NKx2-1 , and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS , TSHR , Tg , and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1 . Conclusion: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures.</description><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Endoderm - cytology</subject><subject>Endoderm - metabolism</subject><subject>Iodide Peroxidase - genetics</subject><subject>Iodide Peroxidase - metabolism</subject><subject>Mice</subject><subject>Multipotent Stem Cells - cytology</subject><subject>Multipotent Stem Cells - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Paired Box Transcription Factors - genetics</subject><subject>Paired Box Transcription Factors - metabolism</subject><subject>PAX8 Transcription Factor</subject><subject>Receptors, Thyrotropin - genetics</subject><subject>Receptors, Thyrotropin - metabolism</subject><subject>Special</subject><subject>Special Article</subject><subject>Symporters - genetics</subject><subject>Symporters - metabolism</subject><subject>Thyroglobulin - genetics</subject><subject>Thyroglobulin - metabolism</subject><subject>Thyroid Gland - cytology</subject><subject>Thyroid Gland - metabolism</subject><subject>Thyroid Nuclear Factor 1</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>1050-7256</issn><issn>1557-9077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUuPFCEUhYnROA9dujW1dFMtFEVRbExMp0cnGePCcWdCeNyaxlDQAjWx_72UPU50ZVhw4Xz3cMlB6BXBG4JH8bbsj5sOk26Dh75_gs4JY7wVmPOntcYMt7xjwxm6yPk7xmQYOX2OzjpKB4xHfo6-3e6PKTrbXEXvnfFQizSr4mJoVLDNb_nOR714F5rdz0OCnFexnj4tvrhDLBBKsws2WqidvvlSYG624H1-gZ5Nymd4-bBfoq9Xu9vtx_bm84fr7fub1vSCl9aCMIYqDAPDHR96O2oQoFVndAcUmNJMjYJMBqwwhAOry06M93oSdho1vUTvTr6HRc9gTR0oKS8Pyc0qHWVUTv6rBLeXd_Fe0oHgvqfV4M2DQYo_FshFzi6b-gUVIC5ZEtoRLjjhuKLtCTUp5pxgenyGYLkmImsick1ErolU_vXfsz3SfyKoAD0B67UKwTvQkMp_bH8BWyScxg</recordid><startdate>20130401</startdate><enddate>20130401</enddate><creator>Ma, Risheng</creator><creator>Latif, Rauf</creator><creator>Davies, Terry F.</creator><general>Mary Ann Liebert, Inc</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130401</creationdate><title>Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells</title><author>Ma, Risheng ; Latif, Rauf ; Davies, Terry F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-de9cc3a0e6502764d8be9eba2cb2e3e5ab5a891fced9c17e5e5edf574bf9df8b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Endoderm - cytology</topic><topic>Endoderm - metabolism</topic><topic>Iodide Peroxidase - genetics</topic><topic>Iodide Peroxidase - metabolism</topic><topic>Mice</topic><topic>Multipotent Stem Cells - cytology</topic><topic>Multipotent Stem Cells - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Paired Box Transcription Factors - genetics</topic><topic>Paired Box Transcription Factors - metabolism</topic><topic>PAX8 Transcription Factor</topic><topic>Receptors, Thyrotropin - genetics</topic><topic>Receptors, Thyrotropin - metabolism</topic><topic>Special</topic><topic>Special Article</topic><topic>Symporters - genetics</topic><topic>Symporters - metabolism</topic><topic>Thyroglobulin - genetics</topic><topic>Thyroglobulin - metabolism</topic><topic>Thyroid Gland - cytology</topic><topic>Thyroid Gland - metabolism</topic><topic>Thyroid Nuclear Factor 1</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Risheng</creatorcontrib><creatorcontrib>Latif, Rauf</creatorcontrib><creatorcontrib>Davies, Terry F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Thyroid (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Risheng</au><au>Latif, Rauf</au><au>Davies, Terry F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells</atitle><jtitle>Thyroid (New York, N.Y.)</jtitle><addtitle>Thyroid</addtitle><date>2013-04-01</date><risdate>2013</risdate><volume>23</volume><issue>4</issue><spage>385</spage><epage>391</epage><pages>385-391</pages><issn>1050-7256</issn><eissn>1557-9077</eissn><abstract>Objective: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors—NKx2 homeobox 1 ( NKx2-1 , formerly called TTF-1 ) and Paired box gene 8 ( Pax8 )—are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter ( NIS ), thyrotropin (TSH) receptor ( TSHR ), thyroglobulin ( Tg ), and thyroid peroxidase ( TPO ) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. Methods: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS , TSHR , Tg , and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. Results: The four thyroid-specific genes NIS , TSHR , Tg , and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR , Tg , and TPO genes was detected in cells expressing just NKx2-1 , and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS , TSHR , Tg , and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1 . Conclusion: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>23360087</pmid><doi>10.1089/thy.2012.0644</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Cell Differentiation
Endoderm - cytology
Endoderm - metabolism
Iodide Peroxidase - genetics
Iodide Peroxidase - metabolism
Mice
Multipotent Stem Cells - cytology
Multipotent Stem Cells - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Paired Box Transcription Factors - genetics
Paired Box Transcription Factors - metabolism
PAX8 Transcription Factor
Receptors, Thyrotropin - genetics
Receptors, Thyrotropin - metabolism
Special
Special Article
Symporters - genetics
Symporters - metabolism
Thyroglobulin - genetics
Thyroglobulin - metabolism
Thyroid Gland - cytology
Thyroid Gland - metabolism
Thyroid Nuclear Factor 1
Transcription Factors - genetics
Transcription Factors - metabolism
title Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells
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