HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/H1915    most recent 00956.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Yamamoto, K. Articles by Ando, J. Search for Related Content PubMed PubMed Citation Articles by Yamamoto, K. Articles by Ando, J.

Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro

¹Department of Biomedical Engineering and ²Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo; ³Stem Cell Research Center, Institute for Frontier Medical Science, Kyoto University, Kyoto; and ⁴Interdisciplinary Science Center, Nihon University, Tokyo, Japan

Submitted 13 September 2004 ; accepted in final form 22 November 2004

Pluripotent embryonic stem (ES) cells are capable of differentiating into all cell lineages, but the molecular mechanisms that regulate ES cell differentiation have not been sufficiently explored. In this study, we report that shear stress, a mechanical force generated by fluid flow, can induce ES cell differentiation. When Flk-1-positive (Flk-1⁺) mouse ES cells were subjected to shear stress, their cell density increased markedly, and a larger percentage of the cells were in the S and G₂-M phases of the cell cycle than Flk-1⁺ ES cells cultured under static conditions. Shear stress significantly increased the expression of the vascular endothelial cell-specific markers Flk-1, Flt-1, vascular endothelial cadherin, and PECAM-1 at both the protein level and the mRNA level, but it had no effect on expression of the mural cell marker smooth muscle -actin, blood cell marker CD3, or the epithelial cell marker keratin. These findings indicate that shear stress selectively promotes the differentiation of Flk-1⁺ ES cells into the endothelial cell lineage. The shear stressed Flk-1⁺ ES cells formed tubelike structures in collagen gel and developed an extensive tubular network significantly faster than the static controls. Shear stress induced tyrosine phosphorylation of Flk-1 in Flk-1⁺ ES cells that was blocked by a Flk-1 kinase inhibitor, SU1498, but not by a neutralizing antibody against VEGF. SU1498 also abolished the shear stress-induced proliferation and differentiation of Flk-1⁺ ES cells, indicating that a ligand-independent activation of Flk-1 plays an important role in the shear stress-mediated proliferation and differentiation by Flk-1⁺ ES cells.

hemodynamic force; blood vessel; vascular endothelial growth factor; mechanical stress; neovascularization

This article has been cited by other articles:

				S. Obi, K. Yamamoto, N. Shimizu, S. Kumagaya, T. Masumura, T. Sokabe, T. Asahara, and J. Ando Fluid shear stress induces arterial differentiation of endothelial progenitor cells J Appl Physiol, January 1, 2009; 106(1): 203 - 211. [Abstract] [Full Text] [PDF]

				S. A. Ruiz and C. S. Chen Emergence of Patterned Stem Cell Differentiation Within Multicellular Structures Stem Cells, November 1, 2008; 26(11): 2921 - 2927. [Abstract] [Full Text] [PDF]

				W. Zheng, L. P. Christensen, and R. J. Tomanek Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H794 - H800. [Abstract] [Full Text] [PDF]

				K. Kawasaki, T. Watabe, H. Sase, M. Hirashima, H. Koide, Y. Morishita, K. Yuki, T. Sasaoka, T. Suda, M. Katsuki, et al. Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells J. Cell Biol., April 3, 2008; 181(1): 131 - 141. [Abstract] [Full Text] [PDF]

				S. M. Nauli, Y. Kawanabe, J. J. Kaminski, W. J. Pearce, D. E. Ingber, and J. Zhou Endothelial Cilia Are Fluid Shear Sensors That Regulate Calcium Signaling and Nitric Oxide Production Through Polycystin-1 Circulation, March 4, 2008; 117(9): 1161 - 1171. [Abstract] [Full Text] [PDF]

				N. Shimizu, K. Yamamoto, S. Obi, S. Kumagaya, T. Masumura, Y. Shimano, K. Naruse, J. K. Yamashita, T. Igarashi, and J. Ando Cyclic strain induces mouse embryonic stem cell differentiation into vascular smooth muscle cells by activating PDGF receptor {beta} J Appl Physiol, March 1, 2008; 104(3): 766 - 772. [Abstract] [Full Text] [PDF]

				L. Zeng, Q. Xiao, A. Margariti, Z. Zhang, A. Zampetaki, S. Patel, M. C. Capogrossi, Y. Hu, and Q. Xu HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells J. Cell Biol., September 25, 2006; 174(7): 1059 - 1069. [Abstract] [Full Text] [PDF]

				M. Schmelter, B. Ateghang, S. Helmig, M. Wartenberg, and H. Sauer Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation FASEB J, June 1, 2006; 20(8): 1182 - 1184. [Abstract] [Full Text] [PDF]

				C. Patterson Even Flow: Shear Cues Vascular Development Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1761 - 1762. [Full Text] [PDF]

				H. Wang, G. M. Riha, S. Yan, M. Li, H. Chai, H. Yang, Q. Yao, and C. Chen Shear Stress Induces Endothelial Differentiation From a Murine Embryonic Mesenchymal Progenitor Cell Line Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1817 - 1823. [Abstract] [Full Text] [PDF]