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

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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. (Blood. 2012;120(13):2733-2744)
Publisher
AMER SOC HEMATOLOGY
Issue Date
2012-09
Language
English
Article Type
Article
Keywords

VASCULAR PROGENITORS; IN-VITRO; SPROUTING ANGIOGENESIS; MICROFLUIDIC PLATFORM; VEGF; PATHWAY; VASCULOGENESIS; ARTERIAL; KINASES; PROTEIN

Citation

BLOOD, v.120, no.13, pp.2733 - 2744

ISSN
0006-4971
DOI
10.1182/blood-2012-04-421610
URI
http://hdl.handle.net/10203/102289
Appears in Collection
ME-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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