Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways
The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell diffe...
Gespeichert in:
| Veröffentlicht in: | Stem cells (Dayton, Ohio) Ohio), 2016-02, Vol.34 (2), p.299-310 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 310 |
|---|---|
| container_issue | 2 |
| container_start_page | 299 |
| container_title | Stem cells (Dayton, Ohio) |
| container_volume | 34 |
| creator | Lee, Hyunwoo Haller, Corinne Manneville, Carole Doll, Thierry Fruh, Isabelle Keller, Caroline Gubser Richards, Shola M. Ibig‐Rehm, Yvonne Patoor, Maude Goette, Marjo Bouchez, Laure C. Mueller, Matthias |
| description | The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (skeletal muscle inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers 3 weeks after induction. Gene expression profiling studies that were carried out for mode of actions analysis showed that SMIs activated genes regulated by the Wnt pathway and inhibited expression of Smad2/3 and Sonic Hedgehog (Shh) target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells from 129 as well as Balb/c and C57Bl/6 to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Shh pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease. Stem Cells 2016;34:299–310 |
| doi_str_mv | 10.1002/stem.2228 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1785246595</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3952653671</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4918-4ba72e0fe89fadd95b22d3d648a7b1fec187bb56739b5faf34f1bcc835c888833</originalsourceid><addsrcrecordid>eNqNkctu1DAUhiMEohdY8ALIEhtYpGM7cewsq2GgI7UCKUVdRr4cNy5O0sZJq3mxPh9OplQICQlvbOl8_nyO_yR5R_AJwZiuwgjtCaVUvEgOCcvLNC-JeBnPuChShsvyIDkK4QZjkjMhXicHtGCcZwIfJo9bA93orNNydH2HeouqVnqPLnoPevIQ0FXjdIO2nZk0oOoneBhlrE9Be0CfnbUwzIr9fdehTauGXd85jarYF1qD9wHdO4lO9ejun58ZG0BX3YhkZ6K8ccr90YChq2ypVIvoDMw1NP01-i7H5kHuwpvklZU-wNun_Tj58WVzuT5Lz7993a5Pz1M9f0GaK8kpYAuitNKYkilKTWaKXEiuiAVNBFeKFTwrFbPSZrklSmuRMS3iyrLj5OPeezv0dxOEsW5d0HEi2UE_hZpwwWhesJL9B1owxgXnOKIf_kJv-mno4iALFVMrFuGnPaWHPoQBbH07uFYOu5rges69nnOv59wj-_7JOKkWzDP5O-gIrPbAg_Ow-7epri43F4vyFxUfuXo</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1765066695</pqid></control><display><type>article</type><title>Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Lee, Hyunwoo ; Haller, Corinne ; Manneville, Carole ; Doll, Thierry ; Fruh, Isabelle ; Keller, Caroline Gubser ; Richards, Shola M. ; Ibig‐Rehm, Yvonne ; Patoor, Maude ; Goette, Marjo ; Bouchez, Laure C. ; Mueller, Matthias</creator><creatorcontrib>Lee, Hyunwoo ; Haller, Corinne ; Manneville, Carole ; Doll, Thierry ; Fruh, Isabelle ; Keller, Caroline Gubser ; Richards, Shola M. ; Ibig‐Rehm, Yvonne ; Patoor, Maude ; Goette, Marjo ; Bouchez, Laure C. ; Mueller, Matthias</creatorcontrib><description>The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (skeletal muscle inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers 3 weeks after induction. Gene expression profiling studies that were carried out for mode of actions analysis showed that SMIs activated genes regulated by the Wnt pathway and inhibited expression of Smad2/3 and Sonic Hedgehog (Shh) target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells from 129 as well as Balb/c and C57Bl/6 to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Shh pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease. Stem Cells 2016;34:299–310</description><identifier>ISSN: 1066-5099</identifier><identifier>EISSN: 1549-4918</identifier><identifier>DOI: 10.1002/stem.2228</identifier><identifier>PMID: 26577380</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Cell Differentiation ; Cellular therapy ; Differentiation ; Embryonic stem cells ; Embryos ; Gene expression ; Hedgehog Proteins - metabolism ; Human Embryonic Stem Cells - cytology ; Human Embryonic Stem Cells - metabolism ; Humans ; Mesoderm ; Mice ; Mouse Embryonic Stem Cells - cytology ; Mouse Embryonic Stem Cells - metabolism ; Muscle Fibers, Fast-Twitch - cytology ; Muscle Fibers, Fast-Twitch - metabolism ; Muscle stem cells ; Musculoskeletal system ; Myogenesis ; Skeletal muscle ; Smad2 Protein - metabolism ; Smad3 Protein - metabolism ; Stem cells ; Wnt Signaling Pathway</subject><ispartof>Stem cells (Dayton, Ohio), 2016-02, Vol.34 (2), p.299-310</ispartof><rights>2015 AlphaMed Press</rights><rights>2015 AlphaMed Press.</rights><rights>2016 AlphaMed Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4918-4ba72e0fe89fadd95b22d3d648a7b1fec187bb56739b5faf34f1bcc835c888833</citedby><cites>FETCH-LOGICAL-c4918-4ba72e0fe89fadd95b22d3d648a7b1fec187bb56739b5faf34f1bcc835c888833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26577380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Hyunwoo</creatorcontrib><creatorcontrib>Haller, Corinne</creatorcontrib><creatorcontrib>Manneville, Carole</creatorcontrib><creatorcontrib>Doll, Thierry</creatorcontrib><creatorcontrib>Fruh, Isabelle</creatorcontrib><creatorcontrib>Keller, Caroline Gubser</creatorcontrib><creatorcontrib>Richards, Shola M.</creatorcontrib><creatorcontrib>Ibig‐Rehm, Yvonne</creatorcontrib><creatorcontrib>Patoor, Maude</creatorcontrib><creatorcontrib>Goette, Marjo</creatorcontrib><creatorcontrib>Bouchez, Laure C.</creatorcontrib><creatorcontrib>Mueller, Matthias</creatorcontrib><title>Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways</title><title>Stem cells (Dayton, Ohio)</title><addtitle>Stem Cells</addtitle><description>The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (skeletal muscle inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers 3 weeks after induction. Gene expression profiling studies that were carried out for mode of actions analysis showed that SMIs activated genes regulated by the Wnt pathway and inhibited expression of Smad2/3 and Sonic Hedgehog (Shh) target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells from 129 as well as Balb/c and C57Bl/6 to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Shh pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease. Stem Cells 2016;34:299–310</description><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Cellular therapy</subject><subject>Differentiation</subject><subject>Embryonic stem cells</subject><subject>Embryos</subject><subject>Gene expression</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Human Embryonic Stem Cells - cytology</subject><subject>Human Embryonic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Mesoderm</subject><subject>Mice</subject><subject>Mouse Embryonic Stem Cells - cytology</subject><subject>Mouse Embryonic Stem Cells - metabolism</subject><subject>Muscle Fibers, Fast-Twitch - cytology</subject><subject>Muscle Fibers, Fast-Twitch - metabolism</subject><subject>Muscle stem cells</subject><subject>Musculoskeletal system</subject><subject>Myogenesis</subject><subject>Skeletal muscle</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - metabolism</subject><subject>Stem cells</subject><subject>Wnt Signaling Pathway</subject><issn>1066-5099</issn><issn>1549-4918</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctu1DAUhiMEohdY8ALIEhtYpGM7cewsq2GgI7UCKUVdRr4cNy5O0sZJq3mxPh9OplQICQlvbOl8_nyO_yR5R_AJwZiuwgjtCaVUvEgOCcvLNC-JeBnPuChShsvyIDkK4QZjkjMhXicHtGCcZwIfJo9bA93orNNydH2HeouqVnqPLnoPevIQ0FXjdIO2nZk0oOoneBhlrE9Be0CfnbUwzIr9fdehTauGXd85jarYF1qD9wHdO4lO9ejun58ZG0BX3YhkZ6K8ccr90YChq2ypVIvoDMw1NP01-i7H5kHuwpvklZU-wNun_Tj58WVzuT5Lz7993a5Pz1M9f0GaK8kpYAuitNKYkilKTWaKXEiuiAVNBFeKFTwrFbPSZrklSmuRMS3iyrLj5OPeezv0dxOEsW5d0HEi2UE_hZpwwWhesJL9B1owxgXnOKIf_kJv-mno4iALFVMrFuGnPaWHPoQBbH07uFYOu5rges69nnOv59wj-_7JOKkWzDP5O-gIrPbAg_Ow-7epri43F4vyFxUfuXo</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Lee, Hyunwoo</creator><creator>Haller, Corinne</creator><creator>Manneville, Carole</creator><creator>Doll, Thierry</creator><creator>Fruh, Isabelle</creator><creator>Keller, Caroline Gubser</creator><creator>Richards, Shola M.</creator><creator>Ibig‐Rehm, Yvonne</creator><creator>Patoor, Maude</creator><creator>Goette, Marjo</creator><creator>Bouchez, Laure C.</creator><creator>Mueller, Matthias</creator><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>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201602</creationdate><title>Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways</title><author>Lee, Hyunwoo ; Haller, Corinne ; Manneville, Carole ; Doll, Thierry ; Fruh, Isabelle ; Keller, Caroline Gubser ; Richards, Shola M. ; Ibig‐Rehm, Yvonne ; Patoor, Maude ; Goette, Marjo ; Bouchez, Laure C. ; Mueller, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4918-4ba72e0fe89fadd95b22d3d648a7b1fec187bb56739b5faf34f1bcc835c888833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Cellular therapy</topic><topic>Differentiation</topic><topic>Embryonic stem cells</topic><topic>Embryos</topic><topic>Gene expression</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Human Embryonic Stem Cells - cytology</topic><topic>Human Embryonic Stem Cells - metabolism</topic><topic>Humans</topic><topic>Mesoderm</topic><topic>Mice</topic><topic>Mouse Embryonic Stem Cells - cytology</topic><topic>Mouse Embryonic Stem Cells - metabolism</topic><topic>Muscle Fibers, Fast-Twitch - cytology</topic><topic>Muscle Fibers, Fast-Twitch - metabolism</topic><topic>Muscle stem cells</topic><topic>Musculoskeletal system</topic><topic>Myogenesis</topic><topic>Skeletal muscle</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - metabolism</topic><topic>Stem cells</topic><topic>Wnt Signaling Pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Hyunwoo</creatorcontrib><creatorcontrib>Haller, Corinne</creatorcontrib><creatorcontrib>Manneville, Carole</creatorcontrib><creatorcontrib>Doll, Thierry</creatorcontrib><creatorcontrib>Fruh, Isabelle</creatorcontrib><creatorcontrib>Keller, Caroline Gubser</creatorcontrib><creatorcontrib>Richards, Shola M.</creatorcontrib><creatorcontrib>Ibig‐Rehm, Yvonne</creatorcontrib><creatorcontrib>Patoor, Maude</creatorcontrib><creatorcontrib>Goette, Marjo</creatorcontrib><creatorcontrib>Bouchez, Laure C.</creatorcontrib><creatorcontrib>Mueller, Matthias</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Stem cells (Dayton, Ohio)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Hyunwoo</au><au>Haller, Corinne</au><au>Manneville, Carole</au><au>Doll, Thierry</au><au>Fruh, Isabelle</au><au>Keller, Caroline Gubser</au><au>Richards, Shola M.</au><au>Ibig‐Rehm, Yvonne</au><au>Patoor, Maude</au><au>Goette, Marjo</au><au>Bouchez, Laure C.</au><au>Mueller, Matthias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways</atitle><jtitle>Stem cells (Dayton, Ohio)</jtitle><addtitle>Stem Cells</addtitle><date>2016-02</date><risdate>2016</risdate><volume>34</volume><issue>2</issue><spage>299</spage><epage>310</epage><pages>299-310</pages><issn>1066-5099</issn><eissn>1549-4918</eissn><abstract>The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (skeletal muscle inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers 3 weeks after induction. Gene expression profiling studies that were carried out for mode of actions analysis showed that SMIs activated genes regulated by the Wnt pathway and inhibited expression of Smad2/3 and Sonic Hedgehog (Shh) target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells from 129 as well as Balb/c and C57Bl/6 to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Shh pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease. Stem Cells 2016;34:299–310</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>26577380</pmid><doi>10.1002/stem.2228</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1066-5099 |
| ispartof | Stem cells (Dayton, Ohio), 2016-02, Vol.34 (2), p.299-310 |
| issn | 1066-5099 1549-4918 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1785246595 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Cell Differentiation Cellular therapy Differentiation Embryonic stem cells Embryos Gene expression Hedgehog Proteins - metabolism Human Embryonic Stem Cells - cytology Human Embryonic Stem Cells - metabolism Humans Mesoderm Mice Mouse Embryonic Stem Cells - cytology Mouse Embryonic Stem Cells - metabolism Muscle Fibers, Fast-Twitch - cytology Muscle Fibers, Fast-Twitch - metabolism Muscle stem cells Musculoskeletal system Myogenesis Skeletal muscle Smad2 Protein - metabolism Smad3 Protein - metabolism Stem cells Wnt Signaling Pathway |
| title | Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T10%3A42%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20Small%20Molecules%20Which%20Induce%20Skeletal%20Muscle%20Differentiation%20in%20Embryonic%20Stem%20Cells%20via%20Activation%20of%20the%20Wnt%20and%20Inhibition%20of%20Smad2/3%20and%20Sonic%20Hedgehog%20Pathways&rft.jtitle=Stem%20cells%20(Dayton,%20Ohio)&rft.au=Lee,%20Hyunwoo&rft.date=2016-02&rft.volume=34&rft.issue=2&rft.spage=299&rft.epage=310&rft.pages=299-310&rft.issn=1066-5099&rft.eissn=1549-4918&rft_id=info:doi/10.1002/stem.2228&rft_dat=%3Cproquest_cross%3E3952653671%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1765066695&rft_id=info:pmid/26577380&rfr_iscdi=true |