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Article: Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes

TitleDistinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
PLoS One, 2011, v. 6 n. 11, article no. e27417 How to Cite?
AbstractBACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
Persistent Identifierhttp://hdl.handle.net/10722/159269
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFu, JDen_US
dc.contributor.authorRushing, SNen_US
dc.contributor.authorLieu, DKen_US
dc.contributor.authorChan, CWen_US
dc.contributor.authorKong, CWen_US
dc.contributor.authorGeng, Len_US
dc.contributor.authorWilson, KDen_US
dc.contributor.authorChiamvimonvat, Nen_US
dc.contributor.authorBoheler, KRen_US
dc.contributor.authorWu, JCen_US
dc.contributor.authorKeller, G-
dc.contributor.authorHajjar, RJ-
dc.contributor.authorLi, RA-
dc.date.accessioned2012-08-16T05:47:35Z-
dc.date.available2012-08-16T05:47:35Z-
dc.date.issued2011en_US
dc.identifier.citationPLoS One, 2011, v. 6 n. 11, article no. e27417en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/10722/159269-
dc.description.abstractBACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.-
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action-
dc.relation.ispartofPLoS Oneen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCell Differentiation-
dc.subject.meshEmbryonic Stem Cells - cytology-
dc.subject.meshHeart Ventricles - cytology - metabolism-
dc.subject.meshMyocytes, Cardiac - cytology - metabolism-
dc.subject.meshVentricular Function - genetics-
dc.titleDistinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytesen_US
dc.typeArticleen_US
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1932-6203 (Electronic)1932-6203 (Linkin&volume=6&issue=11&spage=e27417&epage=&date=2011&atitle=Distinct+roles+of+microRNA-1+and+-499+in+ventricular+specification+and+functional+maturation+of+human+embryonic+stem+cell-derived+cardiomyocytesen_US
dc.identifier.emailChan, CW: camchan@hku.hken_US
dc.identifier.emailKong, CW: marcokong@hku.hken_US
dc.identifier.emailGeng, L: genglin@hku.hken_US
dc.identifier.emailBoheler, KR: bohelerk@hku.hken_US
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hk, ronald.li@mssm.edu-
dc.identifier.authorityChan, CWY=rp01311en_US
dc.identifier.authorityKong, MCW=rp01563en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0027417-
dc.identifier.pmid22110643-
dc.identifier.pmcidPMC3217986-
dc.identifier.scopuseid_2-s2.0-81155134381-
dc.identifier.hkuros203944en_US
dc.identifier.hkuros212198-
dc.identifier.volume6en_US
dc.identifier.issue11, article no. e27417en_US
dc.identifier.eissn1932-6203-
dc.identifier.isiWOS:000297555400043-
dc.publisher.placeUnited States-
dc.identifier.scopusauthoridFu, JD=7401722481-
dc.identifier.scopusauthoridRushing, SN=25121769500-
dc.identifier.scopusauthoridLieu, DK=7003924538-
dc.identifier.scopusauthoridChan, CW=36636982700-
dc.identifier.scopusauthoridKong, CW=36784634200-
dc.identifier.scopusauthoridGeng, L=54585163900-
dc.identifier.scopusauthoridWilson, KD=24726465500-
dc.identifier.scopusauthoridChiamvimonvat, N=7004461965-
dc.identifier.scopusauthoridBoheler, KR=7005975654-
dc.identifier.scopusauthoridWu, JC=37068354600-
dc.identifier.scopusauthoridKeller, G=35427735700-
dc.identifier.scopusauthoridHajjar, RJ=19134434400en_US
dc.identifier.scopusauthoridLi, RA=7404724466-

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