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Article: Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression

TitleFacilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression
Authors
KeywordsAdenovirus
Calcium transients
Ryanodine receptor
Issue Date2009
PublisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpcell.physiology.org/
Citation
American Journal Of Physiology - Cell Physiology, 2009, v. 297 n. 1, p. C152-C159 How to Cite?
AbstractCardiomyocytes (CMs) are nonregenerative. Self-renewable pluripotent human embryonic stem cells (hESCs) can differentiate into CMs for cell-based therapies. We recently reported that Ca2+ handling, crucial to excitation-contraction coupling of hESC-derived CMs (hESC-CMs), is functional but immature. Such immature properties as smaller cytosolic Ca2+ transient amplitudes, slower kinetics, and reduced Ca2+ content of sarcoplasmic reticulum (SR) can be attributed to the differential developmental expression profiles of specific Ca2+ handling and regulatory proteins in hESC-CMs and their adult counterparts. In particular, calsequestrin (CSQ), the most abundant, high-capacity but low-affinity, Ca2+-binding protein in the SR that is anchored to the ryanodine receptor, is robustly expressed in adult CMs but completely absent in hESCCMs. Here we hypothesized that gene transfer of CSQ in hESC-CMs suffices to induce functional improvement of SR. Transduction of hESC-CMs by the recombinant adenovirus Ad-CMV-CSQ-IRES-GFP (Ad-CSQ) significantly increased the transient amplitude, upstroke velocity, and transient decay compared with the control Ad-CMV-GFP (Ad-GFP) and Ad-CMV-CSQΔ-IRES-GFP (Ad-CSQΔ, which mediated the expression of a nonfunctional, truncated version of CSQ) groups. Ad-CSQ increased the SR Ca2+ content but did not alter L-type Ca 2+ current. Pharmacologically, untransduced wildtype, Ad-GFP-, Ad-CSQΔ-, and Ad-CSQ-transduced hESC-CMs behaved similarly. Whereas ryanodine significantly reduced the Ca2+ transient amplitude and slowed the upstroke, thapsigargin slowed the decay. Neither triadin nor junctin was affected. We conclude that CSQ expression in hESC-CMs facilitates Ca 2+ handling maturation. Our results shed insights into the suitability of hESC-CMs for therapies and as certain heart disease models for drug screening. Copyright © 2009 the American Physiological Society.
Persistent Identifierhttp://hdl.handle.net/10722/91566
ISSN
2015 Impact Factor: 3.395
2015 SCImago Journal Rankings: 1.893
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Heart, Lung, and Blood InstituteR01 HL-72857
Stem Cell Program of the University of California, Davis School of Medicine
Shriners Hospital Fellowship
California Institute for Regenerative Medicine
CC Wang Stem Cell Fund
Funding Information:

This work was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL-72857 to R. A. Li), the Stem Cell Program of the University of California, Davis School of Medicine (to R. A. Li), the Shriners Hospital Fellowship (to J. Liu and D. K. Lieu), and the California Institute for Regenerative Medicine (to J. D. Fu and R. A. Li), and CC Wang Stem Cell Fund (to R. A. Li and H. F. Tse).

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Jen_HK
dc.contributor.authorLieu, DKen_HK
dc.contributor.authorSiu, CWen_HK
dc.contributor.authorFu, JDen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLi, RAen_HK
dc.date.accessioned2010-09-17T10:21:28Z-
dc.date.available2010-09-17T10:21:28Z-
dc.date.issued2009en_HK
dc.identifier.citationAmerican Journal Of Physiology - Cell Physiology, 2009, v. 297 n. 1, p. C152-C159en_HK
dc.identifier.issn0363-6143en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91566-
dc.description.abstractCardiomyocytes (CMs) are nonregenerative. Self-renewable pluripotent human embryonic stem cells (hESCs) can differentiate into CMs for cell-based therapies. We recently reported that Ca2+ handling, crucial to excitation-contraction coupling of hESC-derived CMs (hESC-CMs), is functional but immature. Such immature properties as smaller cytosolic Ca2+ transient amplitudes, slower kinetics, and reduced Ca2+ content of sarcoplasmic reticulum (SR) can be attributed to the differential developmental expression profiles of specific Ca2+ handling and regulatory proteins in hESC-CMs and their adult counterparts. In particular, calsequestrin (CSQ), the most abundant, high-capacity but low-affinity, Ca2+-binding protein in the SR that is anchored to the ryanodine receptor, is robustly expressed in adult CMs but completely absent in hESCCMs. Here we hypothesized that gene transfer of CSQ in hESC-CMs suffices to induce functional improvement of SR. Transduction of hESC-CMs by the recombinant adenovirus Ad-CMV-CSQ-IRES-GFP (Ad-CSQ) significantly increased the transient amplitude, upstroke velocity, and transient decay compared with the control Ad-CMV-GFP (Ad-GFP) and Ad-CMV-CSQΔ-IRES-GFP (Ad-CSQΔ, which mediated the expression of a nonfunctional, truncated version of CSQ) groups. Ad-CSQ increased the SR Ca2+ content but did not alter L-type Ca 2+ current. Pharmacologically, untransduced wildtype, Ad-GFP-, Ad-CSQΔ-, and Ad-CSQ-transduced hESC-CMs behaved similarly. Whereas ryanodine significantly reduced the Ca2+ transient amplitude and slowed the upstroke, thapsigargin slowed the decay. Neither triadin nor junctin was affected. We conclude that CSQ expression in hESC-CMs facilitates Ca 2+ handling maturation. Our results shed insights into the suitability of hESC-CMs for therapies and as certain heart disease models for drug screening. Copyright © 2009 the American Physiological Society.en_HK
dc.languageengen_HK
dc.publisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpcell.physiology.org/en_HK
dc.relation.ispartofAmerican Journal of Physiology - Cell Physiologyen_HK
dc.subjectAdenovirusen_HK
dc.subjectCalcium transientsen_HK
dc.subjectRyanodine receptoren_HK
dc.titleFacilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expressionen_HK
dc.typeArticleen_HK
dc.identifier.emailSiu, CW:cwdsiu@hkucc.hku.hken_HK
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authoritySiu, CW=rp00534en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1152/ajpcell.00060.2009en_HK
dc.identifier.pmid19357236-
dc.identifier.pmcidPMC2711646-
dc.identifier.scopuseid_2-s2.0-67650033077en_HK
dc.identifier.hkuros158861-
dc.identifier.hkuros182837-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67650033077&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume297en_HK
dc.identifier.issue1en_HK
dc.identifier.spageC152en_HK
dc.identifier.epageC159en_HK
dc.identifier.eissn1522-1563-
dc.identifier.isiWOS:000268497000017-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLiu, J=14007978900en_HK
dc.identifier.scopusauthoridLieu, DK=7003924538en_HK
dc.identifier.scopusauthoridSiu, CW=7006550690en_HK
dc.identifier.scopusauthoridFu, JD=7401722481en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK

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