WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenit...
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| Veröffentlicht in: | The Journal of clinical investigation 2013-04, Vol.123 (4), p.1647-1661 |
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| container_title | The Journal of clinical investigation |
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| creator | Cui, Lu Guan, Yuan Qu, Zepeng Zhang, Jingfa Liao, Bing Ma, Bo Qian, Jiang Li, Dangsheng Li, Weiye Xu, Guo-Tong Jin, Ying |
| description | Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors. |
| doi_str_mv | 10.1172/JCI65048 |
| format | Article |
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In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI65048</identifier><identifier>PMID: 23524971</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Biomedical research ; Cell Differentiation ; Cell Transformation, Neoplastic - metabolism ; Cell Transformation, Neoplastic - pathology ; Cellular signal transduction ; Embryonic Stem Cells - metabolism ; Embryonic Stem Cells - pathology ; Embryonic Stem Cells - physiology ; Eye Neoplasms - metabolism ; Eye Neoplasms - pathology ; Eye Proteins - metabolism ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Growth ; Hepatocyte Nuclear Factor 1-alpha ; Homeobox Protein SIX3 ; Homeodomain Proteins - metabolism ; Intercellular Signaling Peptides and Proteins - physiology ; Intermediate Filament Proteins - genetics ; Intermediate Filament Proteins - metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Nestin ; Opsins - metabolism ; Paired Box Transcription Factors - metabolism ; PAX6 Transcription Factor ; Photoreceptors ; Repressor Proteins - metabolism ; Retina ; Retina - pathology ; Stem Cell Transplantation ; Stem cells ; T Cell Transcription Factor 1 - genetics ; T Cell Transcription Factor 1 - metabolism ; Transcription Factors - metabolism ; Transcriptome ; Transplantation ; Tumors ; Wnt Signaling Pathway</subject><ispartof>The Journal of clinical investigation, 2013-04, Vol.123 (4), p.1647-1661</ispartof><rights>COPYRIGHT 2013 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Apr 2013</rights><rights>Copyright © 2013, American Society for Clinical Investigation 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c676t-8877e346384ea9b015bd97861d634fdeabf56ec1cabec6e5d51da27c39b77e303</citedby><cites>FETCH-LOGICAL-c676t-8877e346384ea9b015bd97861d634fdeabf56ec1cabec6e5d51da27c39b77e303</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/PMC3613909/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613909/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23524971$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Lu</creatorcontrib><creatorcontrib>Guan, Yuan</creatorcontrib><creatorcontrib>Qu, Zepeng</creatorcontrib><creatorcontrib>Zhang, Jingfa</creatorcontrib><creatorcontrib>Liao, Bing</creatorcontrib><creatorcontrib>Ma, Bo</creatorcontrib><creatorcontrib>Qian, Jiang</creatorcontrib><creatorcontrib>Li, Dangsheng</creatorcontrib><creatorcontrib>Li, Weiye</creatorcontrib><creatorcontrib>Xu, Guo-Tong</creatorcontrib><creatorcontrib>Jin, Ying</creatorcontrib><title>WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.</description><subject>Animals</subject><subject>Biomedical research</subject><subject>Cell Differentiation</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Cellular signal transduction</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Embryonic Stem Cells - pathology</subject><subject>Embryonic Stem Cells - physiology</subject><subject>Eye Neoplasms - metabolism</subject><subject>Eye Neoplasms - pathology</subject><subject>Eye Proteins - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Growth</subject><subject>Hepatocyte Nuclear Factor 1-alpha</subject><subject>Homeobox Protein SIX3</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Intercellular Signaling Peptides and Proteins - physiology</subject><subject>Intermediate Filament Proteins - genetics</subject><subject>Intermediate Filament Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Nestin</subject><subject>Opsins - metabolism</subject><subject>Paired Box Transcription Factors - metabolism</subject><subject>PAX6 Transcription Factor</subject><subject>Photoreceptors</subject><subject>Repressor Proteins - metabolism</subject><subject>Retina</subject><subject>Retina - pathology</subject><subject>Stem Cell Transplantation</subject><subject>Stem cells</subject><subject>T Cell Transcription Factor 1 - genetics</subject><subject>T Cell Transcription Factor 1 - metabolism</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptome</subject><subject>Transplantation</subject><subject>Tumors</subject><subject>Wnt Signaling Pathway</subject><issn>0021-9738</issn><issn>1558-8238</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>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkl9rFDEUxQdR7LYKfgIZEEQfpk4m_2ZehLJUXSkWbLWPIZPcmU2ZSdYkU9pvbwa3tSv7IHkIJL9zcnPvybJXqDxGiFcfvi5XjJakfpItEKV1UVe4fpotyrJCRcNxfZAdhnBdlogQSp5nBxWmFWk4WmRXV98u82B6Kwdj-1xDBD8aCyGP0-i86cEaZeJdLq3Ou8mqaJzNXZefXiwLDd7cgM49RJMM8o13Mx-dDy-yZ50cArzc7kfZj0-nl8svxdn559Xy5KxQjLNY1DXngAnDNQHZtCWirW54zZBmmHQaZNtRBgop2YJiQDVFWlZc4aadhSU-yj7-8d1M7QhagY1eDmLjzSj9nXDSiN0ba9aidzcCM4SbskkG77YG3v2aIEQxmqBgGKQFNwWBMOOkIRTjhL75B712k08fnynCGWpQyf9SvRxAGNu59K6aTcUJJqjBHNO57mIPlboHqUhnoTPpeIc_3sOnpWE0aq_g_Y4gMRFuYy-nEMTq4vv_s-c_d9m3j9g1yCGugxumORdhF9w2VnkXgofuYSioFHNqxX1qE_r68RAfwPuY4t_fkuPH</recordid><startdate>20130401</startdate><enddate>20130401</enddate><creator>Cui, Lu</creator><creator>Guan, Yuan</creator><creator>Qu, Zepeng</creator><creator>Zhang, Jingfa</creator><creator>Liao, Bing</creator><creator>Ma, Bo</creator><creator>Qian, Jiang</creator><creator>Li, Dangsheng</creator><creator>Li, Weiye</creator><creator>Xu, Guo-Tong</creator><creator>Jin, Ying</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</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>BEC</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>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20130401</creationdate><title>WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors</title><author>Cui, Lu ; Guan, Yuan ; Qu, Zepeng ; Zhang, Jingfa ; Liao, Bing ; Ma, Bo ; Qian, Jiang ; Li, Dangsheng ; Li, Weiye ; Xu, Guo-Tong ; Jin, Ying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c676t-8877e346384ea9b015bd97861d634fdeabf56ec1cabec6e5d51da27c39b77e303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Biomedical research</topic><topic>Cell Differentiation</topic><topic>Cell Transformation, Neoplastic - 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In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>23524971</pmid><doi>10.1172/JCI65048</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2013-04, Vol.123 (4), p.1647-1661 |
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| source | MEDLINE; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals Biomedical research Cell Differentiation Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Cellular signal transduction Embryonic Stem Cells - metabolism Embryonic Stem Cells - pathology Embryonic Stem Cells - physiology Eye Neoplasms - metabolism Eye Neoplasms - pathology Eye Proteins - metabolism Gene expression Gene Expression Regulation, Neoplastic Genes Genetic aspects Growth Hepatocyte Nuclear Factor 1-alpha Homeobox Protein SIX3 Homeodomain Proteins - metabolism Intercellular Signaling Peptides and Proteins - physiology Intermediate Filament Proteins - genetics Intermediate Filament Proteins - metabolism Mice Mice, Inbred C57BL Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nestin Opsins - metabolism Paired Box Transcription Factors - metabolism PAX6 Transcription Factor Photoreceptors Repressor Proteins - metabolism Retina Retina - pathology Stem Cell Transplantation Stem cells T Cell Transcription Factor 1 - genetics T Cell Transcription Factor 1 - metabolism Transcription Factors - metabolism Transcriptome Transplantation Tumors Wnt Signaling Pathway |
| title | WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors |
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