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EMBRYONIC STEM CELLS

Functional Activity of the Carboxyl-Terminally Extended Oxytocin Precursor Peptide During Cardiac Differentiation of Embryonic Stem Cells

^aDepartment of Internal Medicine III, University of Cologne, Cologne, Germany;
^bResearch Centre, Centre Hospitalier de l'Université de Montréal Hôtel-Dieu, Montreal, Quebec, Canada;
^cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

Key Words. Embryonic stem cells • Developmental biology • Gene transfer • Growth factors

Correspondence: Jolanta Gutkowska, Ph.D., CHUM-Hôtel-Dieu Research Center, 3850 Saint Urbain, Montreal, Quebec H2W 1T7, Canada. Telephone: 514-890-8000, ext. 12731; Fax: 514-412-7204; e-mail: jolanta.gutkowska{at}umontreal.ca

Received April 20, 2007; accepted for publication October 2, 2007.
First published online in STEM CELLS EXPRESS   October 18, 2007.



The hypothalamic post-translational processing of oxytocin (OT)-neurophysin precursor involves the formation of C-terminally extended OT forms (OT-X) that serve as intermediate prohormones. Despite abundant expression of the entire functional OT system in the developing heart, the biosynthesis and implication of OT prohormones in cardiomyogenesis remain unknown. In the present work, we investigated the involvement of OT-X in cardiac differentiation of embryonic stem (ES) cells. Functional studies revealed the OT receptor-mediated cardiomyogenic action of OT-Gly-Lys-Arg (OT-GKR). To obtain further insight into the mechanisms of OT-GKR-induced cardiac effects, we generated ES cell lines overexpressing the OT-GKR gene and enhanced green fluorescent protein (EGFP). The functionality of the OT-GKR/EGFP construct was assessed by fluorescence microscopy and flow cytometry, with further confirmation by radioimmunoassay and immunostaining. Increased spontaneously beating activity of OT-GKR/EGFP-expressing embryoid bodies and elevated expression of GATA-4 and myosin light chain 2v cardiac genes indicated an inductive effect of endogenous OT-GKR on ES cell-derived cardiomyogenesis. Furthermore, patch-clamp experiments demonstrated induction of ventricular phenotypes in OT-GKR/EGFP-transfected and in OT-GKR-treated cardiomyocytes. Increased connexin 43 protein in OT-GKR/EGFP-expressing cells further substantiated the evidence that OT-GKR modifies cardiac differentiation toward the ventricular sublineage. In conclusion, this report provides new evidence of the biological activity of OT-X, notably OT-GKR, during cardiomyogenic differentiation.

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