Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality
The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a br...
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| Veröffentlicht in: | Development (Cambridge) 2016-12, Vol.143 (23), p.4368-4380 |
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| creator | Zimmerlin, Ludovic Park, Tea Soon Huo, Jeffrey S Verma, Karan Pather, Sarshan R Talbot, Jr, C Conover Agarwal, Jasmin Steppan, Diana Zhang, Yang W Considine, Michael Guo, Hong Zhong, Xiufeng Gutierrez, Christian Cope, Leslie Canto-Soler, M Valeria Friedman, Alan D Baylin, Stephen B Zambidis, Elias T |
| description | The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling. |
| doi_str_mv | 10.1242/dev.138982 |
| format | Article |
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However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.138982</identifier><identifier>PMID: 27660325</identifier><language>eng</language><publisher>England: The Company of Biologists Ltd</publisher><subject>Animals ; Bone Morphogenetic Protein 4 - metabolism ; Cell Differentiation - physiology ; Cell Self Renewal - physiology ; Cells, Cultured ; Cellular Reprogramming - physiology ; Embryonic Stem Cells - cytology ; Germ Layers - embryology ; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors ; Humans ; Induced Pluripotent Stem Cells - cytology ; Janus Kinases - metabolism ; Leukemia Inhibitory Factor - metabolism ; Mice ; STAT3 Transcription Factor - metabolism ; Stem Cells and Regeneration ; Tankyrases - antagonists & inhibitors ; Wnt Signaling Pathway - physiology</subject><ispartof>Development (Cambridge), 2016-12, Vol.143 (23), p.4368-4380</ispartof><rights>2016. 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Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.</description><subject>Animals</subject><subject>Bone Morphogenetic Protein 4 - metabolism</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Self Renewal - physiology</subject><subject>Cells, Cultured</subject><subject>Cellular Reprogramming - physiology</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Germ Layers - embryology</subject><subject>Glycogen Synthase Kinase 3 beta - antagonists & inhibitors</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Janus Kinases - metabolism</subject><subject>Leukemia Inhibitory Factor - metabolism</subject><subject>Mice</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stem Cells and Regeneration</subject><subject>Tankyrases - antagonists & inhibitors</subject><subject>Wnt Signaling Pathway - physiology</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1qGzEUhUVJqR2nmz5A0DIUxpWuND_aBEJofiDQjbMWGo2mVjOjmUgaBz9VHyIvVhk7Jt1ldRbnu4dzOQh9o2RJgcOPxmyWlFWigk9oTnlZZoKCOEFzInKSUSHoDJ2G8IcQwoqy_IJmUBYFYZDPkVop97T1Khhs3drWNtrB4dEP_RBNwAqHqOrO4PXUK4edev27MXjsJm_HBLi486PBLzause3T3cY0uJ2c3uWozsbtGfrcqi6YrwddoMebn6vru-zh1-399dVDpjmlMWs55YLmlJR5XhcsB05ANA0QUKBz0Ey0rAaokwggjeZNooSBRCjNFWULdLnPHae6N41O5bzq5Ohtr_xWDsrK_x1n1_L3sJE5EEo4pICLQ4AfnicTouxt0KbrlDPDFCStioqxqiTsAyjjQhSsFAn9vke1H0Lwpj02okTu5pNpPrmfL8Hn7384om97sX-sFpiP</recordid><startdate>20161201</startdate><enddate>20161201</enddate><creator>Zimmerlin, Ludovic</creator><creator>Park, Tea Soon</creator><creator>Huo, Jeffrey S</creator><creator>Verma, Karan</creator><creator>Pather, Sarshan R</creator><creator>Talbot, Jr, C Conover</creator><creator>Agarwal, Jasmin</creator><creator>Steppan, Diana</creator><creator>Zhang, Yang W</creator><creator>Considine, Michael</creator><creator>Guo, Hong</creator><creator>Zhong, Xiufeng</creator><creator>Gutierrez, Christian</creator><creator>Cope, Leslie</creator><creator>Canto-Soler, M Valeria</creator><creator>Friedman, Alan D</creator><creator>Baylin, Stephen B</creator><creator>Zambidis, Elias T</creator><general>The Company of Biologists Ltd</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3697-3798</orcidid><orcidid>https://orcid.org/0000-0001-5959-2096</orcidid><orcidid>https://orcid.org/0000-0002-2519-1291</orcidid><orcidid>https://orcid.org/0000-0002-4468-6820</orcidid><orcidid>https://orcid.org/0000-0002-6031-0348</orcidid><orcidid>https://orcid.org/0000-0002-0057-9118</orcidid><orcidid>https://orcid.org/0000-0001-5452-254X</orcidid></search><sort><creationdate>20161201</creationdate><title>Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality</title><author>Zimmerlin, Ludovic ; 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Company of Biologists |
| subjects | Animals Bone Morphogenetic Protein 4 - metabolism Cell Differentiation - physiology Cell Self Renewal - physiology Cells, Cultured Cellular Reprogramming - physiology Embryonic Stem Cells - cytology Germ Layers - embryology Glycogen Synthase Kinase 3 beta - antagonists & inhibitors Humans Induced Pluripotent Stem Cells - cytology Janus Kinases - metabolism Leukemia Inhibitory Factor - metabolism Mice STAT3 Transcription Factor - metabolism Stem Cells and Regeneration Tankyrases - antagonists & inhibitors Wnt Signaling Pathway - physiology |
| title | Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality |
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