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a Hubrecht Laboratory, Utrecht, Netherlands;
b Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands;
c Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, Netherlands;
d Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
Key Words. Cardiac • Embryonic • Stem cells • Coculture • Endoderm
Correspondence: Christine Mummery, Ph.D., Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, Netherlands. Telephone: 31-30-2121800; Fax: 31-30-2516464; e-mail: christin{at}niob.knaw.nl
Human embryonic stem cells (hESCs) can differentiate into cardiomyocytes, but the efficiency of this process is low. We routinely induce cardiomyocyte differentiation of the HES-2 cell line by coculture with a visceral endoderm-like cell line, END-2, in the presence of 20% fetal calf serum (FCS). In this study, we demonstrate a striking inverse relationship between cardiomyocyte differentiation and the concentration of FCS during HES-2-END-2 coculture. The number of beating areas in the cocultures was increased 24-fold in the absence of FCS compared with the presence of 20% FCS. An additional 40% increase in the number of beating areas was observed when ascorbic acid was added to serum-free cocultures. The increase in serum-free cocultures was accompanied by increased mRNA and protein expression of cardiac markers and of Isl1, a marker of cardiac progenitor cells. The number of beating areas increased up to 12 days after initiation of coculture of HES-2 with END-2 cells. However, the number of
-actinin–positive cardiomyocytes per beating area did not differ significantly between serum-free cocultures (503 ± 179; mean ± standard error of the mean) and 20% FCS cocultures (312 ± 227). The stimulating effect of serum-free coculture on cardiomyocyte differentiation was observed not only in HES-2 but also in the HES-3 and HES-4 cell lines. To produce sufficient cardiomyocytes for cell replacement therapy in the future, upscaling cardiomyocyte formation from hESCs is essential. The present data provide a step in this direction and represent an improved in vitro model, without interfering factors in serum, for testing other factors that might promote cardiomyocyte differentiation.
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