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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2127.)
© 2007 American Heart Association, Inc.

Vascular Biology

Pathway for Differentiation of Human Embryonic Stem Cells to Vascular Cell Components and Their Potential for Vascular Regeneration

Masakatsu Sone; Hiroshi Itoh; Kenichi Yamahara; Jun K. Yamashita; Takami Yurugi-Kobayashi; Akane Nonoguchi; Yutaka Suzuki; Ting-Hsing Chao; Naoki Sawada; Yasutomo Fukunaga; Kazutoshi Miyashita; Kwijun Park; Naofumi Oyamada; Naoya Sawada; Daisuke Taura; Naohisa Tamura; Yasushi Kondo; Shinji Nito; Hirofumi Suemori; Norio Nakatsuji; Shin-Ichi Nishikawa; Kazuwa Nakao

From the Department of Medicine and Clinical Science (M.S., H.I., K.Y., T.Y-K., A.N., T-H.C., Naok.S., Y.F., K.M., K.P., N.O., Naoy.S., D.T., N.T., K.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Internal Medicine (H.I.), Keio University School of Medicine, Tokyo, Japan; Laboratory of Stem Cell Differentiation (J.K.Y.) and Laboratory of Embryonic Stem Cell Research (H.S.), Stem Cell Research Center, and Department of Development and Differentiation (N.N.), Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Discovery Research Laboratory (Y.S., Y.K., S.N.), Tanabe Seiyaku Co, Ltd, Osaka, Japan; Center for Developmental Biology (S-I.N.), RIKEN, Kobe, Japan.

Correspondence to Hiroshi Itoh, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp

Objective— We demonstrated previously that mouse embryonic stem (ES) cell–derived vascular endothelial growth factor receptor-2 (VEGF-R2)–positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration.

Methods and Results— Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)–negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60–negative cells were also positive for platelet-derived growth factor receptor and β chains and could be effectively differentiated into both VE-cadherin⁺ endothelial cell and -smooth muscle actin⁺ mural cell. VE-cadherin⁺ cells, which were also CD34⁺ and VEGF-R2⁺ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow.

Conclusions— We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

We investigated differentiation kinetics of human ES cells to vascular cell components. We identified the differentiation process from human ES cells to endothelial cells and mural cells and demonstrated the potential of endothelial cells in the early differentiation stage as a cell source for vascular regeneration.

Key Words: angiogenesis • developmental biology • embryonic stem cells • vascular biology • endothelium

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