HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0549v1 25/12/3038    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, J. Articles by Li, R. A. Search for Related Content PubMed PubMed Citation Articles by Liu, J. Articles by Li, R. A.

EMBRYONIC STEM CELLS

Functional Sarcoplasmic Reticulum for Calcium Handling of Human Embryonic Stem Cell-Derived Cardiomyocytes: Insights for Driven Maturation

^aStem Cell Program and
^bDepartment of Cell Biology and Human Anatomy, University of California Davis, Davis, California, USA;
^cInstitute of Pediatric Regenerative Medicine, Shriners Hospital for Children of North America, Sacramento, California, USA

Key Words. Human embryonic stem cells • Cardiomyocytes • Maturation • Ca²⁺ handling • Sarcoplasmic reticulum

Correspondence: Ronald Li, Ph.D., University of California, Davis, Room 650, Shriners Hospital, 2425 Stockton Blvd., Sacramento, California 95817, USA. Telephone: (916) 453-2225; Fax: (916) 453-2238; e-mail: ronaldli{at}ucdavis.edu

Received July 10, 2007; accepted for publication August 29, 2007.
First published online in STEM CELLS EXPRESS   September 13, 2007.



Cardiomyocytes (CMs) are nonregenerative. Self-renewable pluripotent human embryonic stem cells (hESCs) can differentiate into CMs for cell-based therapies. In adult CMs, Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR) is key in excitation-contraction coupling. Therefore, proper Ca²⁺ handling properties of hESC-derived CMs are required for their successful functional integration with the recipient heart. Here, we performed a comprehensive analysis of CMs differentiated from the H1 (H1-CMs) and HES2 (HES2-CMs) hESC lines and human fetal (F) and adult (A) left ventricular (LV) CMs. Upon electrical stimulation, all of H1-, HES2-, and FLV-CMs generated similar Ca²⁺ transients. Caffeine induced Ca²⁺ release in 65% of FLV-CMs and 38% of H1- and HES2-CMs. Ryanodine significantly reduced the electrically evoked Ca²⁺ transient amplitudes of caffeine-responsive but not -insensitive HES2- and H1-CMs and slowed their upstroke; thapsigargin, which inhibits the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, reduced the amplitude of only caffeine-responsive HES2- and H1-CMs and slowed the decay. SERCA2a expression was highest in ALV-CMs but comparable among H1-, HES2-, and FLV-CMs. The Na⁺-Ca²⁺ exchanger was substantially expressed in both HES2- and H1-CMs relative to FLV- and ALV-CMs. RyR was expressed in HES2-, H1-, and FLV-CMs, but the organized pattern for ALV-CMs was not observed. The regulatory proteins junctin, triadin, and calsequestrin were expressed in ALV-CMs but not HES2- and H1-CMs. We conclude that functional SRs are indeed expressed in hESC-CMs, albeit immaturely. Our results may lead to driven maturation of Ca²⁺ handling properties of hESC-CMs for enhanced contractile functions.

Disclosure of potential conflicts of interest is found at the end of this article.