Distinct Roles of MicroRNA-1 and-499 in Ventricular Specification and Functional Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes

被引：140

作者：

Fu, Ji-Dong ^{[1
]}

Rushing, Stephanie N. ^{[1
,2
]}

Lieu, Deborah K. ^{[1
,2
]}

Chan, Camie W. ^{[1
,3
,4
]}

Kong, Chi-Wing ^{[3
,6
,7
]}

Geng, Lin ^{[6
]}

Wilson, Kitchener D. ^{[8
,9
]}

Chiamvimonvat, Nipavan ^{[1
]}

Boheler, Kenneth R. ^{[6
,10
]}

Wu, Joseph C. ^{[8
,9
]}

Keller, Gordon ^{[11
]}

Hajjar, Roger J. ^{[2
]}

Li, Ronald A. ^{[1
,2
,3
,5
,6
,7
]}

机构：

[1] Univ Calif Davis, Sch Med, Davis, CA 95616 USA

[2] Mt Sinai Sch Med, Ctr Cardiovasc Res, New York, NY USA

[3] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China

[4] Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China

[5] Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China

[6] Univ Hong Kong, Stem Cell & Regenerat Med Consortium, Hong Kong, Hong Kong, Peoples R China

[7] Univ Hong Kong, LKS Fac Med, Heart Brain Hormone & Hlth Aging Res Ctr, Hong Kong, Hong Kong, Peoples R China

[8] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA

[9] Stanford Univ, Dept Radiol, Palo Alto, CA 94304 USA

[10] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA

[11] Univ Hlth Network, McEwen Cent Regenerat Med, Toronto, ON, Canada

来源：

PLOS ONE | 2011年 / 6卷 / 11期

基金：

美国国家卫生研究院;

关键词：

MUSCLE-SPECIFIC MICRORNA; TRANSCRIPTION FACTOR; GENE-TRANSFER; DIFFERENTIATION; PACEMAKER; EXPRESSION; HEART; MOUSE; OVEREXPRESSION; DETERMINANTS;

D O I：

10.1371/journal.pone.0027417

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: 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 If (p < 0.05) as signs of functional maturation. Also, LV-miR-1 but not 499 augmented the immature Ca2+ 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.

引用

页数：15

共 53 条

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