Establishment of therapeutic lymphangiogenesis for lymphedema

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390208
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: MUROHARA TOYOAKI 名古屋大学, 医学(系)研究科(研究院), 教授 (90299503)
• Co-Investigator(Kenkyū-buntansha): SHINTANI Satoshi 名古屋大学, 医学系研究科, 講師 (20309777) ; SHIBATA Rei 名古屋大学, 医学系研究科, 特任講師 (70343689)
• Co-Investigator(Renkei-kenkyūsha): KONDO Kazuhisa 名古屋大学, 医学部附属病院, 病院助教 (90644659)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 再生医学 / リンパ浮腫 / リンパ管再生 / リンパ管内皮細胞 / 細胞移植療法 / 間葉系幹細胞 / 脂肪組織由来幹細胞 / サイトカイン

Research Abstract

Lymphedema is a serious clinical problem that occurs after surgical resection of cancers. We report that implantation of adipose-derived regenerative cells (ADRCs) can induce lymphangiogenesis in a mouse model of lymphedema.
ADRCs were isolated from C57BL/6J mice. To examine the efficacy of ADRC implantation in vivo, we established a new mouse model of tail lymphedema. Lymphedema was improved significantly by local injection of ADRCs. Histological analysis revealed that lymphatic capillary density was greater in the ADRC group than in the PBS-injected control group. Tissue expression of vascular endothelial growth factor C (VEGF-C) was greater in the ADRC group than in the control group. ADRCs released VEGF-C, which stimulated lymphangiogenesis. Implantation of ADRCs also enhanced recruitment of M2 macrophages, which served as lymphatic endothelial progenitors. In conclusion, implantation of ADRCs could be a useful treatment option for lymphedema by mediation of lymphangiogenesis.

Research Products

• [Journal Article] Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema (2013)
  • Author(s): Shimizu Y, Shibata R, Ishii M, Ohashi K, Kambara T, Uemura Y, Yuasa D, Kataoka Y, Kihara S, Murohara T, Ouchi N
  • Journal Title: J. Am. Heart Assoc Volume: 2 Pages: e000438
  • Peer Reviewed
• [Journal Article] Therapeutic reendothelialization by induced pluripotent stem cells after vascular injury--brief report (2013)
  • Author(s): Yamamoto T, Shibata R, Ishii M, Kanemura N, Kito T, Suzuki H, Miyake H, Maeda K, Tanigawa T, Ouchi N, Murohara T
  • Journal Title: Arterioscler. Thromb. Vasc. Biol Volume: 33 Pages: 2218-2221
  • Peer Reviewed
• [Journal Article] iPS cell sheets created by a novel magnetite tissue engineering method for reparative angiogenesis (2013)
  • Author(s): Kito T, Shibata R, Ishii M, Suzuki H, Himeno T, Kataoka Y, Yamamura Y, Yamamoto T, Nishio N, Ito S, Numaguchi Y, Tanigawa T, Yamashita JK, Ouchi N, Honda H, Isobe K, Murohara T
  • Journal Title: Sci. Rep Volume: 3 Pages: 1418
  • DOI: 10.1038/srep01418
  • Peer Reviewed
• [Journal Article] Adipose-derived factor ctrp9 attenuates vascular smooth muscle cell proliferation and neointimal formation (2013)
  • Author(s): Uemura Y, Shibata R, Ohashi K, Enomoto T, Kambara T, Yamamoto T, Ogura Y, Yuasa D, Joki Y, Matsuo K, Miyabe M, Kataoka Y, Murohara T, Ouchi N
  • Journal Title: FASEB J Volume: 27 Pages: 25-33
  • Peer Reviewed
• [Journal Article] Stress augments insulin resistance and prothrombotic state : Role of visceral adipose-derived monocyte chemoattractant protein-1 (2012)
  • Author(s): Uchida Y, Takeshita K, Yamamoto K, Kikuchi R, Nakayama T, Nomura M, Cheng XW, Egashira K, Matsushita T, Nakamura H, Murohara T
  • Journal Title: Diabetes Volume: 61 Pages: 1552-1561
  • Peer Reviewed
• [Journal Article] Therapeutic impact of Follistatin-like 1 on myocardial ischemic injury in preclinical animal models (2012)
  • Author(s): Ogura Y, Ouchi N, Ohashi K, Shibata R, Kataoka Y, Kambara T, Kito T, Maruyama S, Yuasa D, Matsuo K, Enomoto T, Uemura Y, Miyabe M, Ishii M, Yamamoto T, Shimizu Y, Walsh K, Murohara T
  • Journal Title: Circulation Volume: 126 Pages: 1728-1738
  • Peer Reviewed
• [Journal Article] Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells (2012)
  • Author(s): Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T
  • Journal Title: J. Am. Heart Assoc Volume: 1 Pages: e000877
  • Peer Reviewed
• [Journal Article] The actin-binding protein girdin and its akt-mediated phosphorylation regulate neointima formation after vascular injury (2011)
  • Author(s): Miyake H, Maeda K, Asai N, Shibata R, Ichimiya H, Isotani-Sakakibara M, Yamamura Y, Kato K, Enomoto A, Takahashi M, Murohara T
  • Journal Title: Circ. Res Volume: 108 Pages: 1170-1179
  • Peer Reviewed
• [Presentation] Adiponectin stimulates lymphangiogenesis and ameliorates secondary lymphedema (2012)
  • Author(s): Shimizu Y, Shibata R, Ohashi K, Ishii M, Shintani S, Murohara T, Ouchi N
  • Organizer: American Heart Association (AHA) Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2012-11-05
• [Presentation] Adipose-derived regenerative cells implantation alleviates lymphedema via augmentation of VEGF-C mediated M2 macrophage mobilization (2012)
  • Author(s): Shimizu Y, Shintani S, Shibata R, Ishii M, Changning H, Hayashida R, Murohara T
  • Organizer: American Heart Association (AHA) Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2012-11-04
• [Presentation] A Novel Therapeutic Strategy for Secondary Lymphedema by Adipose-Derived Regenerative Cells (2012)
  • Author(s): Shimizu Y, Shintani S, Shibata R, Ishii M, Changning H, Murohara T
  • Organizer: Annual Scientific Meeting of the Japanese Circulation Society(第76回日本循環器学会)
  • Place of Presentation: 福岡国際会議場, 福岡市
  • Year and Date: 2012-03-17
• [Presentation] Implantation of adipose-derived regenerative cells enhances lymphangiogenesis and improves secondary lymphedema (2011)
  • Author(s): Shimizu Y, Shintani S, Shibata R, Izumi Y, Ogura Y, Ishii M, Murohara T
  • Organizer: American Heart Association (AHA) Scientific Sessions 2011
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-11-14
• [Presentation] M2 macrophages contribute to postnatal lymphangiogenesis as lymphatic endothelial cell progenitors (2011)
  • Author(s): Shimizu Y, Shintani S, Shibata R, Izumi Y, Ogura Y, Ishii M, Murohara T
  • Organizer: American Heart Association (AHA) Scientific Sessions 2011
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-11-13
• [Presentation] Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells (2011)
  • Author(s): Shimizu Y, Shintani S, Shibata R, Izumi Y, Ogura Y, Ishii M, Murohara T
  • Organizer: The European Society of Cardiology (ESC) Congress 2011
  • Place of Presentation: Paris, France
  • Year and Date: 2011-08-28