Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 9, Pages 3405-3410Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220832110
Keywords
engraftment; surface markers; Stem cells; mature cardiomyocytes; clonal analysis
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Funding
- California Institute for Regenerative Medicine [RCI 00354]
- National Institutes of Health/National Heart, Lung, and Blood Institute Fellowship [5T32 HL00708]
- American College of Cardiology/Pfizer Career Development Award
- Howard Hughes Medical Institute
- California Institute for Regenerative Medicine
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A goal of regenerative medicine is to identify cardiovascular progenitors from human ES cells (hESCs) that can functionally integrate into the human heart. Previous studies to evaluate the developmental potential of candidate hESC-derived progenitors have delivered these cells into murine and porcine cardiac tissue, with inconclusive evidence regarding the capacity of these human cells to physiologically engraft in xenotransplantation assays. Further, the potential of hESC-derived cardiovascular lineage cells to functionally couple to human myocardium remains untested and unknown. Here, we have prospectively identified a population of hESC-derived ROR2(+)/CD13(+)/KDR+/PDGFR alpha(+) cells that give rise to cardiomyocytes, endothelial cells, and vascular smooth muscle cells in vitro at a clonal level. We observed rare clusters of ROR2(+) cells and diffuse expression of KDR and PDGFR alpha in first-trimester human fetal hearts. We then developed an in vivo transplantation model by transplanting second-trimester human fetal heart tissues s.c. into the ear pinna of a SCID mouse. ROR2(+)/CD13(+)/KDR+/PDGFR alpha(+) cells were delivered into these functioning fetal heart tissues: in contrast to traditional murine heart models for cell transplantation, we show structural and functional integration of hESC-derived cardiovascular progenitors into human heart.
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