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Article: Na +/Ca 2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes

TitleNa +/Ca 2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes
Authors
Issue Date2010
PublisherMary Ann Liebert, Inc Publishers. The Journal's web site is located at http://www.liebertpub.com/jht
Citation
Stem Cells And Development, 2010, v. 19 n. 6, p. 773-782 How to Cite?
AbstractIn adult cardiomyocytes (CMs), the Na +/Ca 2+ exchanger (NCX) is a well-defined determinant of Ca 2+ homeostasis. Developmentally, global NCX knockout in mice leads to abnormal myofibrillar organization, electrical defects, and early embryonic death. Little is known about the expression and function of NCX in human heart development. Self-renewable, pluripotent human embryonic stem cells (hESCs) can serve as an excellent experimental model. However, hESC-derived CMs are highly heterogeneous. A stably lentivirus-transduced hESC line (MLC2v-dsRed) was generated to express dsRed under the transcriptional control of the ventricular-restricted myosin light chain-2v (MLC2v) promoter. Electrophysiologically, dsRed+ cells differentiated from MLC2vdsRed hESCs displayed ventricular action potentials (AP), exclusively. Neither atrial nor pacemaker APs were observed. While I Ca-L, I f, and I Kr were robustly expressed, I Ks and I K1 were absent in dsRed+ ventricular hESCCMs. Upon differentiation (7+40 to +90 days), the basal [Ca 2+] i, Ca 2+ transient amplitude, maximum upstroke, and decay velocities significantly increased (P<0.05). The I Ca-L antagonizer nifedipine (1μM) decreased the Ca 2+ transient amplitude (to ∼30%) and slowed the kinetics (by ∼2-fold), but Ca 2+ transients could still be elicited even after complete ICa-L blockade, suggesting the presence of additional Ca 2+ influx(es). Indeed, Ni 2+-sensitive INCX could be recorded in 7+40- and +90-day dsRed+ hESC-CMs, and its densities increased from -1.2±0.6 pA/pF at -120 mV and 3.6±1.0 pA/pF at 60 mV by 6- and 2-folds, respectively. With higher [Ca 2+] i, 7+90-day ventricular hESC-CMs spontaneously but irregularly fired transients upon a single stimulus under an external Na +-free condition; however, without extracellular Na +, nifedipine could completely inhibit Ca 2+ transients. We conclude that I NCX is functionally expressed in developing ventricular hESC-CMs and contributes to their excitation-contraction coupling. © Copyright 2010, Mary Ann Liebert, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/125068
ISSN
2015 Impact Factor: 3.777
2015 SCImago Journal Rankings: 1.703
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthR01 HL72857
University of California
California Institute for Regenerative Medicine
CC Wong Foundation
Funding Information:

This work was supported by grants from the National Institutes of Health-R01 HL72857 (to R.A.L.), the Stem Cell Program of the University of California (to R.A.L.), the California Institute for Regenerative Medicine (to J.D.F. and R.A.L.), and the CC Wong Foundation Stem Cell Fund (to R.A.L.).

References

 

DC FieldValueLanguage
dc.contributor.authorFu, JDen_HK
dc.contributor.authorJiang, Pen_HK
dc.contributor.authorRushing, Sen_HK
dc.contributor.authorLiu, Jen_HK
dc.contributor.authorChiamvimonvat, Nen_HK
dc.contributor.authorLi, RAen_HK
dc.date.accessioned2010-10-31T11:09:37Z-
dc.date.available2010-10-31T11:09:37Z-
dc.date.issued2010en_HK
dc.identifier.citationStem Cells And Development, 2010, v. 19 n. 6, p. 773-782en_HK
dc.identifier.issn1547-3287en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125068-
dc.description.abstractIn adult cardiomyocytes (CMs), the Na +/Ca 2+ exchanger (NCX) is a well-defined determinant of Ca 2+ homeostasis. Developmentally, global NCX knockout in mice leads to abnormal myofibrillar organization, electrical defects, and early embryonic death. Little is known about the expression and function of NCX in human heart development. Self-renewable, pluripotent human embryonic stem cells (hESCs) can serve as an excellent experimental model. However, hESC-derived CMs are highly heterogeneous. A stably lentivirus-transduced hESC line (MLC2v-dsRed) was generated to express dsRed under the transcriptional control of the ventricular-restricted myosin light chain-2v (MLC2v) promoter. Electrophysiologically, dsRed+ cells differentiated from MLC2vdsRed hESCs displayed ventricular action potentials (AP), exclusively. Neither atrial nor pacemaker APs were observed. While I Ca-L, I f, and I Kr were robustly expressed, I Ks and I K1 were absent in dsRed+ ventricular hESCCMs. Upon differentiation (7+40 to +90 days), the basal [Ca 2+] i, Ca 2+ transient amplitude, maximum upstroke, and decay velocities significantly increased (P<0.05). The I Ca-L antagonizer nifedipine (1μM) decreased the Ca 2+ transient amplitude (to ∼30%) and slowed the kinetics (by ∼2-fold), but Ca 2+ transients could still be elicited even after complete ICa-L blockade, suggesting the presence of additional Ca 2+ influx(es). Indeed, Ni 2+-sensitive INCX could be recorded in 7+40- and +90-day dsRed+ hESC-CMs, and its densities increased from -1.2±0.6 pA/pF at -120 mV and 3.6±1.0 pA/pF at 60 mV by 6- and 2-folds, respectively. With higher [Ca 2+] i, 7+90-day ventricular hESC-CMs spontaneously but irregularly fired transients upon a single stimulus under an external Na +-free condition; however, without extracellular Na +, nifedipine could completely inhibit Ca 2+ transients. We conclude that I NCX is functionally expressed in developing ventricular hESC-CMs and contributes to their excitation-contraction coupling. © Copyright 2010, Mary Ann Liebert, Inc.en_HK
dc.languageengen_HK
dc.publisherMary Ann Liebert, Inc Publishers. The Journal's web site is located at http://www.liebertpub.com/jhten_HK
dc.relation.ispartofStem Cells and Developmenten_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThis is a copy of an article published in the Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes © 2010 [copyright Mary Ann Liebert, Inc.]; Stem Cells and Development is available online at: http://www.liebertonline.com.-
dc.subject.meshEmbryonic Stem Cells - cytology - drug effects - metabolism-
dc.subject.meshExcitation Contraction Coupling - drug effects-
dc.subject.meshHeart Ventricles - cytology-
dc.subject.meshMyocytes, Cardiac - cytology - drug effects - metabolism-
dc.subject.meshSodium-Calcium Exchanger - metabolism-
dc.titleNa +/Ca 2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1547-3287&volume=19&issue=6&spage=773&epage=782&date=2010&atitle=Na+/Ca2++exchanger+is+a+determinant+of+excitation-contraction+coupling+in+human+embryonic+stem+cell-derived+ventricular+cardiomyocytes-
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1089/scd.2009.0184en_HK
dc.identifier.pmid19719399-
dc.identifier.pmcidPMC3135244-
dc.identifier.scopuseid_2-s2.0-77954184512en_HK
dc.identifier.hkuros182833en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77954184512&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume19en_HK
dc.identifier.issue6en_HK
dc.identifier.spage773en_HK
dc.identifier.epage782en_HK
dc.identifier.isiWOS:000279033900003-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridFu, JD=7401722481en_HK
dc.identifier.scopusauthoridJiang, P=36022461000en_HK
dc.identifier.scopusauthoridRushing, S=25121769500en_HK
dc.identifier.scopusauthoridLiu, J=8429607500en_HK
dc.identifier.scopusauthoridChiamvimonvat, N=7004461965en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK

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