Cardiomyocytes derived from human embryonic stem cells (hESCs) are promising candidates to regenerate myocardium as a treatment for heart disease. However, this application is limited because of the inability to prospectively identify a pure population of cardiovascular progenitors (CVPs) that is devoid of residual, undifferentiated cells capable of teratoma formation. Furthermore, the potential of hESC-derived cardiovascular lineage cells to functionally couple to human myocardium remains unknown. The purpose of the current study was to test the hypotheses that (i) CVPs derived from hESCs can be isolated based on a set of distinct surface markers and (ii) they can functionally integrate into the human fetal heart. We screened a large panel of monoclonal antibodies to prospectively identify early cardiovascular precursors that emerge from differentiating hESCs based on the expression of surface markers. We discovered four surface markers that highly enrich for CVPs: receptor tyrosine kinase-like orphan receptor family, ROR2, aminopeptidase-N, CD13, kinase insert domain protein receptor, KDR, and platelet-derived growth factor-α, PDGFRα. This quadruple positive population, or QP, gave rise to cardiomyocytes, endothelial cells, and vascular smooth muscle cells in vitro. We observed rare clusters of ROR2+ cells and diffuse expression of KDR and PDGFRα in first trimester human fetal hearts. Upon delivery of the QP cells into murine hearts, they developed into mature cardiomyocytes and endothelial cells, but failed to functionally integrate. While no teratomas were observed in the animals transplanted with QP cells, one out of the seven mice transplanted with the quadruple-negative cells developed teratoma in the heart. In contrast to traditional murine heart models for cell transplantation, delivery of the QP cells into human fetal hearts, heterotopically transplanted into rat’s abdomen, resulted in structural and functional integration of hESC-derived CVPs into human hearts. Taken together, we have shown for the first time that CVPs, defined by four novel surface markers, can structurally and functionally integrate into the electrical syncytia of a human fetal heart upon transplantation.


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  • Received: 05 March 2012
  • Accepted: 28 March 2012
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