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Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes

¹Cardiovascular Research Laboratory, Department of Physiology and Biophysics, ²Department of Anatomy, and ³Department of Obstetrics and Gynecology, Rambam Medical Center, The Bruce Rappaport Faculty of Medicine and the ¹Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, 31096 Haifa, Israel

Submitted 8 January 2003 ; accepted in final form 14 July 2003

Assessment of early ultrastructural development and cell-cycle regulation in human cardiac tissue is significantly hampered by the lack of a suitable in vitro model. Here we describe the possible utilization of human embryonic stem cell (ES) lines for investigation of these processes. With the use of the embryoid body (EB) differentiation system, human ES cell-derived cardiomyocytes at different developmental stages were isolated and their histomorphometric, ultrastructural, and proliferative properties were characterized. Histomorphometric analysis revealed an increase in cell length, area, and length-to-width ratio in late-stage EBs (>35 days) compared with early (10–21 days) and intermediate (21–35 days) stages. This was coupled with a progressive ultrastructural development from an irregular myofibrillar distribution to an organized sarcomeric pattern. Cardiomyocyte proliferation, assessed by double labeling with cardiac-specific antibodies and either [³H]thymidine incorporation or Ki-67 immunolabeling, demonstrated a gradual withdrawal from cell cycle. Hence, the percentage of positively stained nuclei in early-stage cardiomyocytes ([³H]thymidine: 60 ± 10%, Ki-67: 54 ± 23%) decreased to 36 ± 7% and 9 ± 16% in intermediate-stage EBs and to <1% in late-stage cardiomyocytes. In conclusion, a reproducible temporal pattern of early cardiomyocyte proliferation, cell-cycle withdrawal, and ultrastructural maturation was noted in this model. Establishment of this unique in vitro surrogate system may allow to examine the molecular mechanisms underlying these processes and to assess interventions aiming to modify these properties. Moreover, the detailed characterization of the ES cell-derived cardiomyocyte may be crucial for the development of future cell replacement strategies aiming to regenerate functional myocardium.

cell-cycle withdrawal; DNA synthesis; embryoid bodies; sarcomeres

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