Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes
MicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive. We hypothesized that miRs that figure pro...
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| Veröffentlicht in: | PloS one 2011-11, Vol.6 (11), p.e27417-e27417 |
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| creator | Fu, Ji-Dong Rushing, Stephanie N Lieu, Deborah K Chan, Camie W Kong, Chi-Wing Geng, Lin Wilson, Kitchener D Chiamvimonvat, Nipavan Boheler, Kenneth R Wu, Joseph C Keller, Gordon Hajjar, Roger J Li, Ronald A |
| description | MicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive.
We hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p |
| doi_str_mv | 10.1371/journal.pone.0027417 |
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We hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p<0.05) as signs of functional maturation. Also, LV-miR-1 but not -499 augmented the immature Ca(2+) transient amplitude and kinetics. Molecular pathway analyses were performed for further insights.
We conclude that miR-1 and -499 play differential roles in cardiac differentiation of hESCs in a context-dependent fashion. While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0027417</identifier><identifier>PMID: 22110643</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aging ; Analysis ; Animals ; Biology ; Calcium ; Calcium - metabolism ; Cardiomyocytes ; Cell Differentiation ; Cell Line ; Consortia ; Differentiation ; Electrophysiological Phenomena - genetics ; Embryo cells ; Embryonic stem cells ; Embryonic Stem Cells - cytology ; Experiments ; Fetus - cytology ; Fetuses ; Genes ; Heart ; Heart cells ; Heart diseases ; Heart failure ; Heart Ventricles - cytology ; Heart Ventricles - metabolism ; Humans ; Kinetics ; Maturation ; Medicine ; Mice ; MicroRNA ; MicroRNAs ; MicroRNAs - metabolism ; miRNA ; Morphogenesis ; Muscle contraction ; Mutation ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Myogenesis ; Pathogenesis ; Pluripotency ; Ribonucleic acid ; RNA ; Specifications ; Stem cell transplantation ; Stem cells ; Transcription ; Transcription factors ; Ventricle ; Ventricular Function - genetics</subject><ispartof>PloS one, 2011-11, Vol.6 (11), p.e27417-e27417</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Fu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Fu et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-1dbe7b159c6d5037cd4e19c16d7f05e02508766db1f5d0a8b914d5e1cf1b0123</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217986/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217986/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22110643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Rota, Marcello</contributor><creatorcontrib>Fu, Ji-Dong</creatorcontrib><creatorcontrib>Rushing, Stephanie N</creatorcontrib><creatorcontrib>Lieu, Deborah K</creatorcontrib><creatorcontrib>Chan, Camie W</creatorcontrib><creatorcontrib>Kong, Chi-Wing</creatorcontrib><creatorcontrib>Geng, Lin</creatorcontrib><creatorcontrib>Wilson, Kitchener D</creatorcontrib><creatorcontrib>Chiamvimonvat, Nipavan</creatorcontrib><creatorcontrib>Boheler, Kenneth R</creatorcontrib><creatorcontrib>Wu, Joseph C</creatorcontrib><creatorcontrib>Keller, Gordon</creatorcontrib><creatorcontrib>Hajjar, Roger J</creatorcontrib><creatorcontrib>Li, Ronald A</creatorcontrib><title>Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>MicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive.
We hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p<0.05) as signs of functional maturation. Also, LV-miR-1 but not -499 augmented the immature Ca(2+) transient amplitude and kinetics. Molecular pathway analyses were performed for further insights.
We conclude that miR-1 and -499 play differential roles in cardiac differentiation of hESCs in a context-dependent fashion. While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation.</description><subject>Adult</subject><subject>Aging</subject><subject>Analysis</subject><subject>Animals</subject><subject>Biology</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>Cardiomyocytes</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Consortia</subject><subject>Differentiation</subject><subject>Electrophysiological Phenomena - genetics</subject><subject>Embryo cells</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Experiments</subject><subject>Fetus - cytology</subject><subject>Fetuses</subject><subject>Genes</subject><subject>Heart</subject><subject>Heart cells</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Heart Ventricles - cytology</subject><subject>Heart Ventricles - metabolism</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Maturation</subject><subject>Medicine</subject><subject>Mice</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Morphogenesis</subject><subject>Muscle contraction</subject><subject>Mutation</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myogenesis</subject><subject>Pathogenesis</subject><subject>Pluripotency</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Specifications</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Transcription</subject><subject>Transcription factors</subject><subject>Ventricle</subject><subject>Ventricular Function - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8tu1DAUhiMEoqXwBggsIYFYZLBzseMN0qjcRqqoVCq2luPLjCsnHmxnxLwFj4zTSasJ6gJ5Ecf-zn_s3-dk2UsEF6gk6MONG3zP7WLrerWAsCAVIo-yU0TLIscFLB8fzU-yZyHcQFiXDcZPs5OiQAjiqjzN_nwyIZpeROCdVQE4DTojvLv6vswR4L0EeUUpMD3YqT56IwbLPQhbJYw2gkfj-ltKD0kj_XALOh4Hf9hJapuh4z1QXev3rjcChKg6IJS1uVTe7JQEgntpXLd3Yh9VeJ490dwG9WL6nmXXXz5fn3_LLy6_rs6XF7kgNYk5kq0iLaqpwLKGJRGyUogKhCXRsFawqGFDMJYt0rWEvGkpqmStkNCohagoz7LXB9mtdYFNXgaGSlSgmtBiJFYHQjp-w7bedNzvmeOG3S44v2bcRyOsYoJCrLBGhNK2grBtWl0LWMjxUETrUevjlG1oOyXFaCW3M9H5Tm82bO12rCySaIOTwLtJwLtfgwqRdSaMLvJeuSEwCmuKS1qPqd78Qz58uYla83R-02uX0opRky0rghtcNNVILR6g0pAqFUmqO23S-izg_SwgMVH9jms-hMBWP67-n738OWffHrEbxW3cBGeHscjCHKwOYCrhELzS9x4jyMa2uXODjW3DprZJYa-O3-c-6K5Pyr-MTxSE</recordid><startdate>20111116</startdate><enddate>20111116</enddate><creator>Fu, Ji-Dong</creator><creator>Rushing, Stephanie N</creator><creator>Lieu, Deborah K</creator><creator>Chan, Camie W</creator><creator>Kong, Chi-Wing</creator><creator>Geng, Lin</creator><creator>Wilson, Kitchener D</creator><creator>Chiamvimonvat, Nipavan</creator><creator>Boheler, Kenneth R</creator><creator>Wu, Joseph C</creator><creator>Keller, Gordon</creator><creator>Hajjar, Roger J</creator><creator>Li, Ronald A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20111116</creationdate><title>Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes</title><author>Fu, Ji-Dong ; Rushing, Stephanie N ; Lieu, Deborah K ; Chan, Camie W ; Kong, Chi-Wing ; Geng, Lin ; Wilson, Kitchener D ; Chiamvimonvat, Nipavan ; Boheler, Kenneth R ; Wu, Joseph C ; Keller, Gordon ; Hajjar, Roger J ; Li, Ronald A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-1dbe7b159c6d5037cd4e19c16d7f05e02508766db1f5d0a8b914d5e1cf1b0123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Aging</topic><topic>Analysis</topic><topic>Animals</topic><topic>Biology</topic><topic>Calcium</topic><topic>Calcium - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fu, Ji-Dong</au><au>Rushing, Stephanie N</au><au>Lieu, Deborah K</au><au>Chan, Camie W</au><au>Kong, Chi-Wing</au><au>Geng, Lin</au><au>Wilson, Kitchener D</au><au>Chiamvimonvat, Nipavan</au><au>Boheler, Kenneth R</au><au>Wu, Joseph C</au><au>Keller, Gordon</au><au>Hajjar, Roger J</au><au>Li, Ronald A</au><au>Rota, Marcello</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-11-16</date><risdate>2011</risdate><volume>6</volume><issue>11</issue><spage>e27417</spage><epage>e27417</epage><pages>e27417-e27417</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>MicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive.
We hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p<0.05) as signs of functional maturation. Also, LV-miR-1 but not -499 augmented the immature Ca(2+) transient amplitude and kinetics. Molecular pathway analyses were performed for further insights.
We conclude that miR-1 and -499 play differential roles in cardiac differentiation of hESCs in a context-dependent fashion. While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22110643</pmid><doi>10.1371/journal.pone.0027417</doi><tpages>e27417</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-11, Vol.6 (11), p.e27417-e27417 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1312157922 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adult Aging Analysis Animals Biology Calcium Calcium - metabolism Cardiomyocytes Cell Differentiation Cell Line Consortia Differentiation Electrophysiological Phenomena - genetics Embryo cells Embryonic stem cells Embryonic Stem Cells - cytology Experiments Fetus - cytology Fetuses Genes Heart Heart cells Heart diseases Heart failure Heart Ventricles - cytology Heart Ventricles - metabolism Humans Kinetics Maturation Medicine Mice MicroRNA MicroRNAs MicroRNAs - metabolism miRNA Morphogenesis Muscle contraction Mutation Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Myogenesis Pathogenesis Pluripotency Ribonucleic acid RNA Specifications Stem cell transplantation Stem cells Transcription Transcription factors Ventricle Ventricular Function - genetics |
| title | Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes |
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