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1 Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
3 Stem Cell Research Center, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan
4 Interdisciplinary Science Center, Nihon University, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: joji{at}m.u-tokyo.ac.jp.
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 paper, 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 phase and G2-M phase 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, VE-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
SM-
-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 tube-like 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 an 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.
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