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Article: Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

TitleMechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes
Authors
Issue Date2013
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
Citation
Circulation, 2013, v. 6 n. 1, p. 191-201 How to Cite?
AbstractBACKGROUND: Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. METHODS AND RESULTS: Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated (I(Na)(+)/I(CaL)(+)/I(Kr)(+)/I(NCX)(+)/I(f)(+)/I(to)(+)/I(K1)(-)/I(Ks)(-)), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K(+) current (I(K1)) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba(2+)-sensitive I(K1) and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation. CONCLUSIONS: By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.
Persistent Identifierhttp://hdl.handle.net/10722/169256
ISSN
2015 Impact Factor: 17.047
2015 SCImago Journal Rankings: 7.853
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLieu, DKen_US
dc.contributor.authorFu, JDen_US
dc.contributor.authorChiamvimonvat, Nen_US
dc.contributor.authorTung, KCen_US
dc.contributor.authorMcNerney, GPen_US
dc.contributor.authorHuser, Ten_US
dc.contributor.authorKeller, Gen_US
dc.contributor.authorKong, CWen_US
dc.contributor.authorLi, RAen_US
dc.date.accessioned2012-10-18T08:47:10Z-
dc.date.available2012-10-18T08:47:10Z-
dc.date.issued2013en_US
dc.identifier.citationCirculation, 2013, v. 6 n. 1, p. 191-201en_US
dc.identifier.issn0009-7322-
dc.identifier.urihttp://hdl.handle.net/10722/169256-
dc.description.abstractBACKGROUND: Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. METHODS AND RESULTS: Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated (I(Na)(+)/I(CaL)(+)/I(Kr)(+)/I(NCX)(+)/I(f)(+)/I(to)(+)/I(K1)(-)/I(Ks)(-)), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K(+) current (I(K1)) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba(2+)-sensitive I(K1) and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation. CONCLUSIONS: By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.-
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org-
dc.relation.ispartofCirculationen_US
dc.subject.meshCell Differentiation-
dc.subject.meshEmbryonic Stem Cells - metabolism-
dc.subject.meshInduced Pluripotent Stem Cells - metabolism-
dc.subject.meshMyocytes, Cardiac - metabolism-
dc.subject.meshPluripotent Stem Cells - metabolism-
dc.titleMechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytesen_US
dc.typeArticleen_US
dc.identifier.emailKong, CW: marcokong@hku.hken_US
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hken_US
dc.identifier.authorityKong, CW=rp01563en_US
dc.identifier.authorityLi, RA=rp01352en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/CIRCEP.111.973420-
dc.identifier.pmid23392582-
dc.identifier.pmcidPMC3757253-
dc.identifier.hkuros212208en_US
dc.identifier.hkuros239691-
dc.identifier.volume6-
dc.identifier.issue1-
dc.identifier.spage191-
dc.identifier.epage201-
dc.identifier.isiWOS:000320670700029-
dc.publisher.placeUnited States-

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