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(Circulation. 2003;107:1912.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Ascorbic Acid Enhances Differentiation of Embryonic Stem Cells Into Cardiac Myocytes

Tomosaburo Takahashi, MD; Bernadette Lord, BS; P. Christian Schulze, MD; Ryan M. Fryer, PhD; Satinder S. Sarang, PhD; Steven R. Gullans, PhD; Richard T. Lee, MD

From the Cardiovascular Division (T.T., P.C.S., B.L., R.T.L.) and Center for Neurological Diseases (R.M.F., S.S.S., S.R.G.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Richard T. Lee, MD, Partners Research Facility, 65 Landsdowne St, Cambridge, MA 02139. E-mail rlee{at}rics.bwh.harvard.edu

Background— Embryonic stem (ES) cells are capable of self-renewal and differentiation into cellular derivatives of all 3 germ layers. In appropriate culture conditions, ES cells can differentiate into specialized cells, including cardiac myocytes, but the efficiency is typically low and the process is incompletely understood.

Methods and Results— We evaluated a chemical library for its potential to induce cardiac differentiation of ES cells in the absence of embryoid body formation. Using ES cells stably transfected with cardiac-specific -cardiac myosin heavy chain (MHC) promoter-driven enhanced green fluorescent protein (EGFP), 880 compounds approved for human use were screened for their ability to induce cardiac differentiation. Treatment with ascorbic acid, also known as vitamin C, markedly increased the number of EGFP-positive cells, which displayed spontaneous and rhythmic contractile activity and stained positively for sarcomeric myosin and -actinin. Furthermore, ascorbic acid induced the expression of cardiac genes, including GATA4, -MHC, and ß-MHC in untransfected ES cells in a developmentally controlled manner. This effect of ascorbic acid on cardiac differentiation was not mimicked by the other antioxidants such as N-acetylcysteine, Tiron, or vitamin E.

Conclusions— Ascorbic acid induces cardiac differentiation in ES cells. This study demonstrates the potential for chemically modifying the cardiac differentiation program of ES cells.

Key Words: stem cells • ascorbic acid • myocytes

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