Analysis for organ-specific vascular patterning

• Project/Area Number: 19H03397
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: Keio University
• Principal Investigator: KUBOTA Yoshiaki 慶應義塾大学, 医学部(信濃町), 教授 (50348687)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 血管新生 / VEGF / 歯 / がん / FLRT2 / 腫瘍 / 血管 / 血管内皮細胞

Outline of Research at the Start

あらゆる臓器の生存、恒常性維持に血管は必須である。発生過程にこの血管ネットワークが張り巡らされる過程は、極めて秩序だったプロセスを以て進行する。教科書的にこの過程は、①脈管形成、②血管新生、③リモデリングという3つの素過程に分け、説明される。しかしながら、臓器によって異なる血管パターニングの多様性がいかにして獲得されるかは、この3つのステップでは説明できず不明である。本研究は、解剖学・細胞生物学・生化学にin vivoイメージングを取り入れ、各臓器における組織成長よって生じる物理的な力、場の不均衡性および流動性、VEGF受容体の使い分けの観点から、血管多様性獲得の普遍原理を解明する。

Outline of Final Research Achievements

In vertebrates, the vascular network develops throughout the body to meet the demand of oxygen and nutrients in tissues, and to secrete organotypic paracrine molecules, known as angiocrine factors, driving cell differentiation and tissue morphogenesis. Recent advances in the imaging technique and single cell transcriptomics comprehensively uncovered the vascular cell heterogeneity ensuring the functional diversity of organotypic vasculature. In this study, we uncovered the cellular and molecular basis of cell-to-cell communication regulating angiogenesis in the skeletal system in particular teeth, the hardest tissue in our bodies (Matsubara et al., J Exp Med 2022). Moreover we identified an inter-endothelial junction molecule which could be a novel therapeutic target for cancer therapy (Ando et al., J Clin Invest 2022).

Academic Significance and Societal Importance of the Research Achievements

歯の血管の解析で見出された細胞メカニズム、網羅的に同定された血管由来の象牙芽細胞成熟因子などの解析をさらに進めることによって、虫歯・歯周病により失われた歯の再生への応用が期待される。また腫瘍血管の研究成果については、血管ががん細胞を転移させるユニークな仕組みを解明したものであり、ヒトでこのFLRT2の働きを特異的に抑えられる薬剤が開発されれば、VEGF阻害剤では不十分であった、がん転移を効率的に抑える分子標的薬となることが期待される。さらには、免疫チェックポイント阻害剤をがんの奥まで深達させ、その効果を最大限にさせるための、「地ならし」的な併用療法への応用も期待される。

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University of Connecticut/University of Utah(米国)
• [Int'l Joint Research] KAIST/Seoul National University(韓国)
• [Int'l Joint Research] INSERM(フランス)
• [Journal Article] Coupling of angiogenesis and odontogenesis orchestrates tooth mineralization in mice (2022)
  • Author(s): Matsubara T, Iga T, Sugiura Y, Kusumoto D, Sanosaka T, Tai-Nagara I, Takeda N, Fong GH, Ito K, Ema M, Okano H, Kohyama J, Suematsu M, *Kubota Y.
  • Journal Title: J Exp Med Volume: 219 Issue: 4
  • DOI: 10.1084/jem.20211789
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes (2022)
  • Author(s): Harada Y, Sujino T, Miyamoto K, Nomura E, Yoshimatsu Y, Tanemoto S, Umeda S, Ono K, Mikami Y, Nakamoto N, Takabayashi K, Hosoe N, Ogata H, Ikenoue T, Hirao A, Kubota Y, Kanai T.
  • Journal Title: iScience Volume: 25 Issue: 4 Pages: 104021-104021
  • DOI: 10.1016/j.isci.2022.104021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic Deletion of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells Leads to Immediate Disruption of Tumor Vessels and Aggravation of Hypoxia. (2021)
  • Author(s): Kido Y, Ando T, Iga T, Ema M, *Kubota Y, *Tai-Nagara I.
  • Journal Title: Am J Pathol. Volume: 9440 Issue: 2 Pages: 00511-3
  • DOI: 10.1016/j.ajpath.2021.11.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Blood and lymphatic systems are segregated by the FLCN tumor suppressor (2020)
  • Author(s): Tai-Nagara I, Hasumi Y, Kusumoto D, Hasumi H, Okabe K, Ando T, Matsuzaki F, Itoh F, Saya H, Liu C, Li W, Mukouyama Y, Linehan WM, Liu X, Hirashima M, Suzuki Y, Funasaki S, Satou Y, Furuya M, Baba M, Kubota Y.
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 6314-6314
  • DOI: 10.1038/s41467-020-20156-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tamoxifen-Activated CreERT Impairs Retinal Angiogenesis Independently of Gene Deletion (2020)
  • Author(s): Brash JT, Bolton RL, Rashbrook VS, Denti L, Kubota Y, *Ruhrberg C
  • Journal Title: Circulation Research Volume: 127 Issue: 6 Pages: 849-850
  • DOI: 10.1161/circresaha.120.317025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nonmuscle myosin 2 regulates cortical stability during sprouting angiogenesis (2020)
  • Author(s): Ma X, Uchida Y, Wei T, Liu C, Adams RH, Kubota Y, Gutkind JS, Mukouyama YS, *Adelstein RS.
  • Journal Title: Molecular Biology of the Cell Volume: 31 Issue: 18 Pages: 1974-1987
  • DOI: 10.1091/mbc.e20-03-0175
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Macrophages fine-tune pupil shape during development (2020)
  • Author(s): Takahashi M, Misaki M, Shibata S, Iga T, Shindo T, Tai-Nagara I, Hirata A, Ogawa M, Miyamoto T, Nakagawa T, Ema M, Ichiyama Y, Shima DT, Hozumi K, Nishimura S, Kubota Y
  • Journal Title: Dev Biol Volume: 464 Issue: 2 Pages: 137-144
  • DOI: 10.1016/j.ydbio.2020.06.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuron-derived VEGF contributes to cortical and hippocampal development independently of VEGFR1/2-mediated neurotrophism. (2020)
  • Author(s): Okabe K, Fukada H, Tai-Nagara I, Ando T, Honda T, Nakajima K, Takeda N, Fong GH, Ema M, Kubota Y.
  • Journal Title: Dev Biol. Volume: 459(2) Issue: 2 Pages: 65-71
  • DOI: 10.1016/j.ydbio.2019.11.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Neurovascular guidance cue in tumor angiogenesis. (2021)
  • Author(s): Yoshiaki Kubota
  • Organizer: International Symposium of Interactions at the Neurovascular Interface
  • Int'l Joint Research / Invited
• [Presentation] Cell-to-cell communication governing organotypic vasculature (2021)
  • Author(s): Yoshiaki Kubota
  • Organizer: 11th International Kloster Seeon Meeting “Angiogenesis”
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms for the separation of blood and lymphatic systems (2021)
  • Author(s): Yoshiaki Kubota
  • Organizer: CRC1366 “Vascular Control of Organ Function” International Meeting
  • Int'l Joint Research / Invited
• [Presentation] 臓器特異的血管パターニングと組織修復 (2021)
  • Author(s): 久保田義顕
  • Organizer: 第42回日本炎症再生医学会
  • Invited
• [Presentation] 臓器特異的血管形成と細胞間相互作用 (2021)
  • Author(s): 久保田義顕
  • Organizer: 第6回日本肺高血圧・肺循環学会
  • Invited
• [Presentation] 血管の発生と創傷治癒 (2020)
  • Author(s): 久保田義顕
  • Organizer: 第50回日本創傷治癒学会
  • Invited
• [Presentation] 血管・リンパ管の発生と病態 (2020)
  • Author(s): 久保田義顕
  • Organizer: 横浜市立大学大学院医学セミナー
  • Invited
• [Presentation] Cell-to-cell communication regulating angiogenesis and lymphangiogenesis (2020)
  • Author(s): 久保田義顕
  • Organizer: The 21st International Vascular Biology Meeting.
  • Int'l Joint Research / Invited
• [Presentation] Cellular and molecular basis of the neurovascular link (2020)
  • Author(s): 久保田義顕
  • Organizer: 第42回日本血栓止血学会学術集会
  • Invited
• [Presentation] 血管・リンパ管の発生と病態 (2020)
  • Author(s): 久保田義顕
  • Organizer: 第19回日本再生医療学会学術集会
  • Invited
• [Presentation] Cellular and molecular basis of the neurovascular link. (2019)
  • Author(s): Yoshiaki Kubota
  • Organizer: Asia Australia Vascular Biology Meeting
  • Int'l Joint Research / Invited
• [Remarks] 研究室ホームページ
  • URL: http://www.keiovascular.com/
• [Remarks] ラボwebサイト
  • URL: http://www.keiovascular.com/