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EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS

Notch Inhibition Promotes Human Embryonic Stem Cell-Derived Cardiac Mesoderm Differentiation

^aInstitute of Reproductive Medicine and Population, Medical Research Center, and
^bDepartments of Obstetrics and Gynecology,
^eInternal Medicine, and
^gPhysiology, Seoul National University College of Medicine, Seoul, Korea;
^cDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA;
^dClinical Research Institute, Seoul National University Hospital, Seoul, Korea;
^fDepartment of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea

Key Words. Human embryonic stem cell • Notch • -Secretase inhibitor • Cardiac mesoderm

Correspondence: Correspondence: Young Min Choi, M.D., Ph.D., Institute of Reproductive Medicine and Population, Medical Research Center, Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-ku, Seoul 110-810, Korea. Telephone: 82-2-2072-2385; Fax: 82-2-762-3599; e-mail: ymchoi{at}snu.ac.kr

Received on December 12, 2007; accepted for publication on August 12, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

The roles of Notch signaling in cardiac differentiation from murine embryonic stem cells have been well documented. We investigated whether Notch signaling plays a similar role in human embryonic stem cells (hESCs). Although, as previously reported, blocking Notch signaling via the addition of -secretase inhibitor (GSI) alone failed to affect hESC differentiation, we found that GSI plus reduced-volume culture medium (GSI/RVCM) accelerated mesodermal differentiation. GSI/RVCM conditions simultaneously suppressed commitment toward neuroectodermal lineages. Furthermore, sustained inhibition of Notch signaling further enhanced differentiation into cardiac mesoderm. Spontaneous beating activity was typically observed from 12 days after initiation of GSI treatment in RVCM. Moreover, hESC-derived cardiomyocytes expressed connexin 43 and possessed spontaneous calcium oscillations and cardiomyocyte beats coupled to neonatal rat cardiomyocytes when cocultured. These findings strongly suggest a distinct role for Notch signaling in the induction and specification of hESC-derived cardiac mesoderm in vitro.

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