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Molecular and functional evidence of HCN4 and caveolin-3 interaction during cardiomyocyte differentiation from human embryonic stem cells.
MedLine Citation:
PMID:  23311301     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Maturation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) is accompanied by changes in ion channel expression, with relevant electrophysiological consequences. In rodent cardiomyocytes, the properties of HCN4, a major f-channel isoform, depends on association with caveolin-3 (Cav3). To date, no information exists on changes in Cav3 expression and its associative relationship with HCN4 upon hESC-CM maturation. We hypothesize that Cav3 expression and its compartmentalization with HCN4 channels during hESC-CM maturation accounts for the progression of f-current properties toward adult phenotypes. To address this, hESC were differentiated into spontaneously beating CM and examined at ~30, ~60 and ~110 days of differentiation. Human adult and fetal CM served as references. HCN4 and Cav3 expression and localization were analyzed by qPCR and immunocyto/histochemistry. F-current was measured in patch-clamped single cells. HCN4 and Cav3 co-localize in adult human atrial and ventricular CM, but not in fetal CM. Protein and mRNA for Cav3 were not detected in undifferentiated hESC, but expression increased during hESC-CM maturation. At 110 days, HCN4 appeared to be co-localized with Cav3. Voltage-dependent activation of the f-current was significantly more positive in fetal CM and 60-day hESC-CM (midpoint activation, V<sub>1/2</sub>, ~ -82mV) than in 110-day hESC-CM or adult CM (V<sub>1/2</sub> ~ -100mV). In the latter cells, caveolae disruption reversed voltage-dependence toward a more positive, or immature phenotype, with V<sub>1/2</sub> at -75mV, while in fetal CM voltage-dependence was not affected. Our data show, for the first time, a developmental change in HCN4-Cav3 association in hESC-CM. Cav3 expression and its association with ionic channels likely represent a crucial step of cardiac maturation.
Authors:
Alexis Bosman; Laura Sartiani; Valentina Spinelli; Martina Del Lungo; Francesca Stillitano; Daniele Nosi; Alessandro Mugelli; Elisabetta Cerbai; Marisa Jaconi
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-11
Journal Detail:
Title:  Stem cells and development     Volume:  -     ISSN:  1557-8534     ISO Abbreviation:  Stem Cells Dev.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197107     Medline TA:  Stem Cells Dev     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
University of Geneva, Pathology and Immunology, 1 rue Michel-Servet, Geneva 1211, Geneva, Geneva, Switzerland, 1211, +61432494777; alexis.bosman@unige.ch.
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