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(Circulation Research. 2007;100:263.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Tissue Engineering of Vascularized Cardiac Muscle From Human Embryonic Stem Cells

Oren Caspi^*, Ayelet Lesman^*, Yaara Basevitch, Amira Gepstein, Gil Arbel, Irit Huber Manhal Habib, Lior Gepstein, Shulamit Levenberg

From the Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine and the Rappaport Family Institute for Research in the Medical Sciences (O.C., A.G., G.A., I.H., M.H., L.G.), The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology; Department of Biomedical Engineering (A.L., Y.B., S.L.) and Biotechnology Interdisciplinary Unit (Y.B.), Technion-Israel Institute of Technology; and Cardiology Department (L.G.), Rambam Medical Center, Haifa, Israel.

Correspondence to Shulamit Levenberg, PhD, The Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel. E-mail shulamit{at}bm.technion.ac.il; and Lior Gepstein, MD, PhD. The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Efron St. POB 9649, Haifa, Israel, 31096. Email mdlior@tx.technion.ac.il

Transplantation of a tissue-engineered heart muscle represents a novel experimental therapeutic paradigm for myocardial diseases. However, this strategy has been hampered by the lack of sources for human cardiomyocytes and by the scarce vasculature in the ischemic area limiting the engraftment and survival of the transplanted muscle. Beyond the necessity of endothelial capillaries for the delivery of oxygen and nutrients to the grafted muscle tissue, interactions between endothelial and cardiomyocyte cells may also play a key role in promoting cell survival and proliferation. In the present study, we describe the formation of synchronously contracting engineered human cardiac tissue derived from human embryonic stem cells containing endothelial vessel networks. The 3D muscle consisted of cardiomyocytes, endothelial cells (ECs), and embryonic fibroblasts (EmFs). The formed vessels were further stabilized by the presence of mural cells originating from the EmFs. The presence of EmFs decreased EC death and increased EC proliferation. Moreover, the presence of endothelial capillaries augmented cardiomyocyte proliferation and did not hamper cardiomyocyte orientation and alignment. Immunostaining, ultrastructural analysis (using transmission electron microscopy), RT-PCR, pharmacological, and confocal laser calcium imaging studies demonstrated the presence of cardiac-specific molecular, ultrastructural, and functional properties of the generated tissue constructs with synchronous activity mediated by action potential propagation through gap junctions. In summary, this is the first report of the construction of 3D vascularized human cardiac tissue that may have unique applications for studies of cardiac development, function, and tissue replacement therapy.

Key Words: embryonic stem cells • tissue engineering • angiogenesis

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