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Affiliation |
Faculty of Medicine School of Medicine Department of Medical Sciences, Vascular and cellular dynamics |
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Professor |
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Laboratory Address |
5200 Kihara, Kiyotake-cho, Miyazaki-city, Miyazaki 889-1692 |
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Laboratory Phone number |
+81-985-85-0985 |
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Contact information |
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Homepage |
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External Link |
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NISHIYAMA Koichi
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Research Interests 【 display / non-display 】
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vascular basement membrane
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微小血管ネットワーク
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Angiogenesis
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Vascular endothelial cell
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Blood flow
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Mathematical model
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Quantitative analysis
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Mechanical stimuli
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Live imaging
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pericyte
Research Areas 【 display / non-display 】
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Life Science / Biomedical engineering
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Life Science / Cell biology
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Life Science / Molecular biology
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Life Science / Pathological biochemistry
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Life Science / Biophysics
Education 【 display / non-display 】
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Kumamoto University Faculty of Medicine
- 1992.4
Campus Career 【 display / non-display 】
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University of Miyazaki Faculty of Medicine School of Medicine Department of Medical Sciences, Vascular and cellular dynamics Professor
2021.06 - Now
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University of Miyazaki Faculty of Medicine School of Medicine Function control study course tumor biochemistry field Professor
2021.04 - 2021.05
External Career 【 display / non-display 】
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Kumamoto University Lecturer
2014.4 - 2016.3
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Kumamoto University International Research Center for Medical Sciences Chief Researcher
2014 - 2021.3
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The University of Tokyo Graduate School of Medicine Assistant Professor
2006.4 - 2014.3
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The University of Tokyo Graduate School of Medicine Researcher
2005.4 - 2006.3
Professional Memberships 【 display / non-display 】
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日本発生生物学会
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日本血管生物医学会
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日本癌学会
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日本生化学会
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日本生体医工学会
Papers 【 display / non-display 】
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Watanabe-Takano H., Kato K., Oguri-Nakamura E., Ishii T., Kobayashi K., Murata T., Tsujikawa K., Miyata T., Kubota Y., Hanada Y., Nishiyama K., Watabe T., Fässler R., Ishii H., Mochizuki N., Fukuhara S.
Nature Communications 15 ( 1 ) 2024.12
Publishing type：Research paper (scientific journal) Publisher：Nature Communications
Alveologenesis is a spatially coordinated morphogenetic event, during which alveolar myofibroblasts surround the terminal sacs constructed by epithelial cells and endothelial cells (ECs), then contract to form secondary septa to generate alveoli in the lungs. Recent studies have demonstrated the important role of alveolar ECs in this morphogenetic event. However, the mechanisms underlying EC-mediated alveologenesis remain unknown. Herein, we show that ECs regulate alveologenesis by constructing basement membranes (BMs) acting as a scaffold for myofibroblasts to induce septa formation through activating mechanical signaling. Rap1, a small GTPase of the Ras superfamily, is known to stimulate integrin-mediated cell adhesions. EC-specific Rap1-deficient (Rap1iECKO) mice exhibit impaired septa formation and hypo-alveolarization due to the decreased mechanical signaling in myofibroblasts. In Rap1iECKO mice, ECs fail to stimulate integrin β1 to recruit Collagen type IV (Col-4) into BMs required for myofibroblast-mediated septa formation. Consistently, EC-specific integrin β1-deficient mice show hypo-alveolarization, defective mechanical signaling in myofibroblasts, and disorganized BMs. These data demonstrate that alveolar ECs promote integrin β1-mediated Col-4 recruitment in a Rap1-dependent manner, thereby constructing BMs acting as a scaffold for myofibroblasts to induce mechanical signal-mediated alveologenesis. Thus, this study unveils a mechanism of organ morphogenesis mediated by ECs through intrinsic functions.
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第1土曜特集 "かたちづくり" を制御する分子メカニズム 形態形成と多細胞動態 血管新生における血流による物理的力の役割
花田 保之, 西山 功一
医学のあゆみ 290 ( 1 ) 42 - 46 2024.7
Publishing type：Research paper (scientific journal) Publisher：医歯薬出版
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第5土曜特集 血管･リンパ管研究の最前線と治療への展開 血管研究のフロンティア 再構成解析系を駆使した血流による血管新生の生体力学機序の解明
西山 功一
医学のあゆみ 289 ( 13 ) 1093 - 1098 2024.6
Publishing type：Research paper (scientific journal) Publisher：医歯薬出版
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Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice
Yamamoto K., Watanabe-Takano H., Oguri-Nakamura E., Matsuno H., Horikami D., Ishii T., Ohashi R., Kubota Y., Nishiyama K., Murata T., Mochizuki N., Fukuhara S.
FASEB Journal 37 ( 12 ) 2023.12
Publishing type：Research paper (scientific journal) Publisher：FASEB Journal
Vascular permeability is dynamically but tightly controlled by vascular endothelial (VE)-cadherin-mediated endothelial cell–cell junctions to maintain homeostasis. Thus, impairments of VE-cadherin-mediated cell adhesions lead to hyperpermeability, promoting the development and progression of various disease processes. Notably, the lungs are a highly vulnerable organ wherein pulmonary inflammation and infection result in vascular leakage. Herein, we showed that Rap1, a small GTPase, plays an essential role for maintaining pulmonary endothelial barrier function in mice. Endothelial cell-specific Rap1a/Rap1b double knockout mice exhibited severe pulmonary edema. They also showed vascular leakage in the hearts, but not in the brains. En face analyses of the pulmonary arteries and 3D-immunofluorescence analyses of the lungs revealed that Rap1 potentiates VE-cadherin-mediated endothelial cell–cell junctions through dynamic actin cytoskeleton reorganization. Rap1 inhibits formation of cytoplasmic actin bundles perpendicularly binding VE-cadherin adhesions through inhibition of a Rho-ROCK pathway-induced activation of cytoplasmic nonmuscle myosin II (NM-II). Simultaneously, Rap1 induces junctional NM-II activation to create circumferential actin bundles, which anchor and stabilize VE-cadherin at cell–cell junctions. We also showed that the mice carrying only one allele of either Rap1a or Rap1b out of the two Rap1 genes are more vulnerable to lipopolysaccharide (LPS)-induced pulmonary vascular leakage than wild-type mice, while activation of Rap1 by administration of 007, an activator for Epac, attenuates LPS-induced increase in pulmonary endothelial permeability in wild-type mice. Thus, we demonstrate that Rap1 plays an essential role for maintaining pulmonary endothelial barrier functions under physiological conditions and provides protection against inflammation-induced pulmonary vascular leakage.
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特集 新組織学シリーズⅢ:血管とリンパ管 Ⅰ.血管･リンパ管研究の多様なアプローチ In vitro再構成モデルを用いた血管新生における血流力学作用の解析
西山 功一
生体の科学 73 ( 6 ) 517 - 522 2022.12
Publishing type：Research paper (scientific journal) Publisher：株式会社医学書院
MISC 【 display / non-display 】
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血流に起因する内腔圧による創傷治癒過程の血管新生の新たな制御機構
福原茂朋, 弓削進弥, 西山功一, 有馬勇一郎, 花田保之, 花田三四郎, 石井智裕, 若山勇紀, 辻田和也, 横川隆司, 三浦岳, 望月直樹
日本生化学会大会(Web) 93rd 2020
Language：Japanese Publishing type：Rapid communication, short report, research note, etc. (scientific journal)
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内腔圧の機械的刺激により制御される創傷治癒での血管新生
弓削進弥, 西山功一, 有馬勇一郎, 花田保之, 花田三四郎, 石井智裕, 若山勇紀, 辻田和也, 横川隆司, 三浦岳, 望月直樹, 福原茂朋
日本生化学会大会(Web) 93rd 2020
Language：Japanese Publishing type：Rapid communication, short report, research note, etc. (scientific journal)
Grant-in-Aid for Scientific Research 【 display / non-display 】
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Angiogenic machinery via concerted biomechanical control by blood flow pericyte
Grant number：19H04446 2021.04 - 2024.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B) Grant-in-Aid for Scientific Research (B)
Authorship：Principal investigator
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Reproduction of kidney glomerulus structure and function using human iPS cells-derived organoid and vascular chip
Grant number：21K19487 2021.04 - 2023.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory) Grant-in-Aid for Challenging Research (Exploratory)
Authorship：Principal investigator
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ペリサイト消失網膜における炎症と線維化の細胞・分子機構の解明
Grant number：19H03437 2019.04 - 2022.03
日本学術振興会 科学研究費助成事業 基盤研究(B) 基盤研究(B)
植村 明嘉, 西山 功一
Authorship：Coinvestigator(s)
抗PDGFRβ抗体を腹腔内に単回投与して、ペリサイトを消失させた新生仔マウス網膜では、①内皮細胞の炎症反応、②内在性ミクログリアの活性化と骨髄由来マクロファージの浸潤、③血管透過性の亢進、④網膜剥離の発症、⑤活性化型ミクログリアの網膜下への移動、⑥急性炎症から慢性炎症への移行、⑦網膜下の線維化が、順に進行する。こうした過程で、抗CSF1R抗体を投与してミクログリアを消失させると、線維化が抑制されることから、網膜下に移行した活性化型ミクログリアが線維化を誘導することが明らかとなった。さらに単細胞RNAseq解析により、線維化誘導ミクログリアがM2極性化していることが明らかとなった。
Available Technology 【 display / non-display 】
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血管新生のしくみの解明と医療応用
物流ネットワークとしての血管形成とその破綻による病気の理解と制御
血流がある生命現象の試験管内モデルの開発と医学・薬学への応用Home Page： 医学部機能制御学講座血管動態制御学分野
Related fields where technical consultation is available：1．血管新生の解析全般 2．タイムラプスイメージングによる分子・細胞動態の定量的解析 3．ホールマウント免疫染色と画像解析、定量化 4．血管チップを使ったオルガノイド、組織の培養 5．血管チップを使った力学刺激の評価、医療応用
Message：医学・生物学にとらわれない視点で、多くの共同研究者とともに学際的な研究を推進しています。興味を持たれた方はお気軽にお声掛けください。