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      ROCK suppression promotes differentiation and expansion of endothelial cells from embryonic stem cell-derived Flk1(+) mesodermal precursor cells.


      Amides, pharmacology, Animals, Blotting, Western, Cell Adhesion, drug effects, Cell Differentiation, Cell Movement, Cell Proliferation, Cells, Cultured, Collagen, metabolism, Drug Combinations, Embryonic Stem Cells, cytology, Endothelial Cells, Enzyme Inhibitors, Flow Cytometry, Fluorescent Antibody Technique, Laminin, Mesoderm, Mice, Neovascularization, Physiologic, Proteoglycans, Pyridines, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, rho-Associated Kinases, antagonists & inhibitors

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          Successful differentiation and expansion of endothelial cells (ECs) from embryonic stem cell (ESC)-derived Flk1(+) mesodermal precursor cells (MPCs) requires supplementation of vascular endothelial growth factor-A (VEGF-A). While analyzing VEGF-A/VEGFR2 downstream signaling pathway that underlies the VEGF-A-induced differentiation and expansion of ECs, we fortuitously found that Rho-associated protein kinase (ROCK) inhibitor Y27632 profoundly promoted the differentiation and expansion of ECs from Flk1(+) MPCs while reducing the differentiation and expansion of mural cells. The ROCK suppression-induced expansion of ECs appears to have resulted from promotion of proliferation of ECs via activation of PI3-kinase-Akt signaling. The ECs obtained by the combination of ROCK suppression and VEGF-A supplementation faithfully expressed most pan-EC surface makers, and phenotypic analyses revealed that they were differentiated toward arterial EC. Further incubation of the ICAM2(+) ECs with Y27632 and VEGF-A for 2 days promoted expansion of ECs by 6.5-fold compared with those incubated with only VEGF-A. Importantly, the ROCK suppression-induced ECs displayed neovasculogenic abilities in vitro and in vivo. Thus, supplementation of ROCK inhibitor Y27632 along with VEGF-A in 2D Matrigel culture system provides a simple, efficient, and versatile method for obtaining ample amount of ESC-derived ECs at high purity suitable for use in therapeutic neovascularization.

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