Mechanisms of lymphatic differentiation from mouse embryonic stem cells

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17570153
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: The University of Tokyo
• Principal Investigator: WATANABE Tetsuro The University of Tokyo, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (00334235)
• Project Period (FY): 2005 – 2006
• Keywords: blood vessels / lymphatic vessels / embryonic stem cells / regenerative medicine / cancer

Research Abstract

During embryonic lymphatic development, a homeobox transcription factor Prox1 plays important roles in sprouting and migration of a subpopulation of blood vessel endothelial cells (BECs) towards VEGF-C expressing cells. However, effects of Prox1 on endothelial cellular behavior remain to be elucidated. Here we show that Prox1, via induction of integrin α9 expression, inhibits sheet formation and stimulates motility of endothelial cells (mouse embryonic stem cell-derived endothelial cells and human umbilical venous endothelial cells : HUVECs). Prox1-expressing BECs preferentially migrated toward VEGF-C and PDGF-BB up-regulation of the expression of integrin α9 and VEGF receptor 3 (VEGFR3), and that of PDGF receptor β (PDGFRβ), respectively. In mouse embryos, expression of VEGFR3 and integrin α9 is increased in Prox1-expressing lymphatic endothelial cells (LECs) compared to BECs. Knockdown of Prox1 expression in human LECs led to decrease in the expression of integrin α9, VEGFR3 and PDGFRβ, resulting in the decreased chemotaxes toward VEGF-C and PDGF-BB. These findings suggest that Prox1 plays important roles in conferring and maintaining the characteristics of LECs by modulating multiple signaling cascades, and that integrin α9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.

Research Products

• [Journal Article] Prox1 Induces Lymphatic Endothelial Differentiation via Integrin α9 and Other Signaling Cascades. (2007)
  • Author(s): Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, Hirashima M, Morisada T, Oike Y, Araie M, Niwa H, Kubo H, Suda T, Miyazono K
  • Journal Title: Molecular Biology of the Cell. 18 Pages: 1421-1429
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activin/Nodal signaling is involved in propagation of mouse embryonic stem cells. (2007)
  • Author(s): Ogawa K, Saito, A, Matsui H, Suzuki H, Ohtsuka S, Shimosato D, Morishita, Watabe T, Niwa H, Miyazono K
  • Journal Title: Journal of Cell Science. 120 Pages: 55-65
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prox1 Induces Lymphatic Endothelial Differentiation via Integrin α9 and Other Signaling Cascades. (2007)
  • Author(s): Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, Hirashima M, Morisada T, Oike Y, Araie M, Niwa H, Kubo H, Suda T, Miyazono K.
  • Journal Title: Molecular Biology of the Cell 18 Pages: 1421-1429
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activin/Nodal signaling is involved in propagation of mouse embryonic stem cells. (2007)
  • Author(s): Ogawa K, Saito A, Matsui H, Suzuki H, Ohtsuka S, Shimosato D, Morishita, Watabe T, Niwa H, Miyazono K.
  • Journal Title: Journal of Cell Science 120 Pages: 55-65
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of Smad7 Expression on Metastasis of Mouse Mammary Carcinoma JygMC(A) Cells. (2005)
  • Author(s): Azuma H, Ehata S, Miyazaki H, Watahe T, Maruyama O, Imamura T, Sakamoto T, Kiyama S, Kiyama Y, Ubai T, Inamoto T, Takahara S, Itoh Y, Otsuki Y, Katsuoka Y, Miyazono K, Horie S
  • Journal Title: Journal of National Cancer Institute 97 Pages: 1734-1746
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. (2005)
  • Author(s): Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, Miyazono K, Miyazawa K
  • Journal Title: Journal of Cell Science 118 Pages: 3759-3768
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fluid Shear Stress Induces Differentiation of Flk-1-Positive Embryonic Stem Cells into Vascular Endothelial Cells In Vitro. (2005)
  • Author(s): Yamamoto K, Sokabe T, Watabe T, Miyazono K, Yamashita JK, ON S, Ohura N, Matsushita A, Kamiya A, Ando
  • Journal Title: American Journal of Physiology Heart Circulation Physiology. 288 Pages: 915-924
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells. (2005)
  • Author(s): Suzuki H, Watabe T, Miyazawa K, Kato M, Miyazono K
  • Journal Title: Blood 105 Pages: 2372-2379
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of Smad7 Expression on Metastasis of Mouse Mammary Carcinoma JygMC(A) Cells. (2005)
  • Author(s): Azuma H, Ehata S, Miyazaki H, Watabe T, Maruyama O, Imamura T, Sakamoto T, Kiyama S, Kiyama Y, Ubai T, Inamoto T, Takahara S, Itoh Y, Otsuka Y, Katsuoka Y, Miyazono K, Horie S.
  • Journal Title: Journal of National Cancer Institute 97 Pages: 1734-1746
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. (2005)
  • Author(s): Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, Miyazono K, Miyazawa K.
  • Journal Title: Journal of Cell Science 118 Pages: 3759-3768
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fluid Shear Stress Induces Differentiation of Flk-1-Positive Embryonic Stem Cells into Vascular Endothelial Cells In Vitro. (2005)
  • Author(s): Yamamoto K, Sokabe T, Watabe T, Miyazono K, Yamashita JK, Obi S, Ohura N, Matsushita A, Kamiya A, Ando J.
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology 288 Pages: 915-924
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells. (2005)
  • Author(s): Suzuki H, Watabe T, Miyazawa K, Kato M, Miyazono K.
  • Journal Title: Blood 105 Pages: 2372-2379
  • Description: 「研究成果報告書概要(欧文)」より