山下　忠紘 （ヤマシタ　タダヒロ）

Yamashita, Tadahiro

写真a

所属（所属キャンパス）

理工学部 システムデザイン工学科 （矢上）

職名

准教授

外部リンク
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経歴 【 表示 ／ 非表示 】

  • 2013年11月
    -
    2018年03月

    ETH Zürich, Department of Health Sciences and Technology, Postdoctoral researcher

  • 2018年04月
    -
    2021年03月

    慶應義塾大学 理工学部 システムデザイン工学科, 助教(有期)

  • 2021年04月
    -
    継続中

    慶應義塾大学 理工学部 システムデザイン工学科, 専任講師

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学歴 【 表示 ／ 非表示 】

  • 2008年03月

    東京大学, 工学部, 応用化学科

    大学, 卒業

  • 2010年03月

    東京大学, 工学系研究科, バイオエンジニアリング専攻

    大学院, 修了, 修士

  • 2013年09月

    東京大学, 工学系研究科, バイオエンジニアリング専攻

    大学院, 修了, 博士

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学位 【 表示 ／ 非表示 】

  • 学士(工学), 東京大学, 2008年03月

  • 修士(工学), 東京大学, 2010年03月

  • 博士(工学), 東京大学, 2013年09月

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 生体医工学

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研究キーワード 【 表示 ／ 非表示 】

  • メカノバイオロジー

  • 界面科学

  • 組織工学

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著書 【 表示 ／ 非表示 】

  • Material-based Mechanobiology

    Ryosuke Matsuzawa, Midori Takeuchi, Takuya Nishina, Tadahiro Yamashita, The Royal Society of Chemistry, 2022年08月,  ページ数： 26

    担当範囲: Chapter 10. Curvature Mechanobiology,  担当ページ： 213-238 原著者： Jun Nakanishi, Koichiro Uto

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論文 【 表示 ／ 非表示 】

  • Construction of highly vascularized hepatic spheroids of primary hepatocytes via pro-angiogenic strategy in vitro

    Huang Y.H., Watanabe M., Yamashita T., Sudo R.

    Biofabrication 17 （ 3 ）  2025年07月

    ISSN  17585082

    　概要を見る

    Primary hepatocytes are widely recognized for their ability to accurately represent the in vivo hepatocyte phenotype. However, traditional avascular primary hepatocyte culture models are limited by inadequate mass transfer, which leads to a rapid decline in hepatocyte function and survival. To address these challenges, vascularization of hepatic spheroids is crucial for enhancing oxygen and nutrient supply, thereby enabling the construction of larger and more complex hepatic tissues in vitro. In this study, we achieved vascularization of hepatic spheroids containing freshly isolated primary hepatocytes by incorporating fibroblasts as a source of paracrine factors to induce angiogenesis. Multicellular spheroids composed of primary hepatocytes and fibroblasts were formed in non-adhesive concave wells, and one of the spheroids was subsequently embedded in a fibrin-collagen hydrogel within a microfluidic device. Endothelial cells were then seeded onto adjacent microfluidic channels. They formed microvascular networks that extended toward and penetrated the hepatic spheroid. The vascularized hepatic spheroid closely mimicked hepatic sinusoids, with hepatocytes in close contact with microvessels. Moreover, the vascularized spheroid exhibited significantly enhanced hepatic function, specifically albumin secretion and urea synthesis. Our findings provide insights into the establishment of highly vascularized hepatic spheroids in vitro, which is crucial for constructing scalable hepatic tissues in the context of biofabrication.

  • Ex vivo SIM-AFM measurements reveal the spatial correlation of stiffness and molecular distributions in 3D living tissue

    Shioka I., Morita R., Yagasaki R., Wuergezhen D., Yamashita T., Fujiwara H., Okuda S.

    Acta Biomaterialia 189   351 - 365 2024年11月

    ISSN  17427061

    　概要を見る

    Living tissues each exhibit a distinct stiffness, which provides cells with key environmental cues that regulate their behaviors. Despite this significance, our understanding of the spatiotemporal dynamics and the biological roles of stiffness in three-dimensional tissues is currently limited due to a lack of appropriate measurement techniques. To address this issue, we propose a new method combining upright structured illumination microscopy (USIM) and atomic force microscopy (AFM) to obtain precisely coordinated stiffness maps and biomolecular fluorescence images of thick living tissue slices. Using mouse embryonic and adult skin as a representative tissue with mechanically heterogeneous structures inside, we validate the measurement principle of USIM-AFM. Live measurement of tissue stiffness distributions revealed the highly heterogeneous mechanical nature of skin, including nucleated/enucleated epithelium, mesenchyme, and hair follicle, as well as the role of collagens in maintaining its integrity. Furthermore, quantitative analysis comparing stiffness distributions in live tissue samples with those in preserved tissues, including formalin-fixed and cryopreserved tissue samples, unveiled the distinct impacts of preservation processes on tissue stiffness patterns. This series of experiments highlights the importance of live mechanical testing of tissue-scale samples to accurately capture the true spatiotemporal variations in mechanical properties. Our USIM-AFM technique provides a new methodology to reveal the dynamic nature of tissue stiffness and its correlation with biomolecular distributions in live tissues and thus could serve as a technical basis for exploring tissue-scale mechanobiology. Statement of significance: Stiffness, a simple mechanical parameter, has drawn attention in understanding the mechanobiological principles underlying the homeostasis and pathology of living tissues. To explore tissue-scale mechanobiology, we propose a technique integrating an upright structured illumination microscope and an atomic force microscope. This technique enables live measurements of stiffness distribution and fluorescent observation of thick living tissue slices. Experiments revealed the highly heterogeneous mechanical nature of mouse embryonic and adult skin in three dimensions and the previously unnoticed influences of preservation techniques on the mechanical properties of tissue at microscopic resolution. This study provides a new technical platform for live stiffness measurement and biomolecular observation of tissue-scale samples with micron-scale resolution, thus contributing to future studies of tissue- and organ-scale mechanobiology.

  • Multicellular dynamics on structured surfaces: Stress concentration is a key to controlling complex microtissue morphology on engineered scaffolds

    Matsuzawa R., Matsuo A., Fukamachi S., Shimada S., Takeuchi M., Nishina T., Kollmannsberger P., Sudo R., Okuda S., Yamashita T.

    Acta Biomaterialia （Acta Biomaterialia）  166   301 - 316 2023年08月

    ISSN  17427061

    　概要を見る

    Tissue engineers have utilised a variety of three-dimensional (3D) scaffolds for controlling multicellular dynamics and the resulting tissue microstructures. In particular, cutting-edge microfabrication technologies, such as 3D bioprinting, provide increasingly complex structures. However, unpredictable microtissue detachment from scaffolds, which ruins desired tissue structures, is becoming an evident problem. To overcome this issue, we elucidated the mechanism underlying collective cellular detachment by combining a new computational simulation method with quantitative tissue-culture experiments. We first quantified the stochastic processes of cellular detachment shown by vascular smooth muscle cells on model curved scaffolds and found that microtissue morphologies vary drastically depending on cell contractility, substrate curvature, and cell-substrate adhesion strength. To explore this mechanism, we developed a new particle-based model that explicitly describes stochastic processes of multicellular dynamics, such as adhesion, rupture, and large deformation of microtissues on structured surfaces. Computational simulations using the developed model successfully reproduced characteristic detachment processes observed in experiments. Crucially, simulations revealed that cellular contractility-induced stress is locally concentrated at the cell-substrate interface, subsequently inducing a catastrophic process of collective cellular detachment, which can be suppressed by modulating cell contractility, substrate curvature, and cell-substrate adhesion. These results show that the developed computational method is useful for predicting engineered tissue dynamics as a platform for prediction-guided scaffold design. Statement of significance: Microfabrication technologies aiming to control multicellular dynamics by engineering 3D scaffolds are attracting increasing attention for modelling in cell biology and regenerative medicine. However, obtaining microtissues with the desired 3D structures is made considerably more difficult by microtissue detachments from scaffolds. This study reveals a key mechanism behind this detachment by developing a novel computational method for simulating multicellular dynamics on designed scaffolds. This method enabled us to predict microtissue dynamics on structured surfaces, based on cell mechanics, substrate geometry, and cell-substrate interaction. This study provides a platform for the physics-based design of micro-engineered scaffolds and thus contributes to prediction-guided biomaterials design in the future.

  • How the mechanobiology orchestrates the iterative and reciprocal ECM-cell cross-talk that drives microtissue growth

    Benn M.C., Pot S.A., Moeller J., Yamashita T., Fonta C.M., Orend G., Kollmannsberger P., Vogel V.

    Science Advances （Science Advances）  9 （ 13 ）  2023年03月

    　概要を見る

    Controlled tissue growth is essential for multicellular life and requires tight spatiotemporal control over cell proliferation and differentiation until reaching homeostasis. As cells synthesize and remodel extracellular matrix, tissue growth processes can only be understood if the reciprocal feedback between cells and their environment is revealed. Using de novo–grown microtissues, we identified crucial actors of the mechanoregulated events, which iteratively orchestrate a sharp transition from tissue growth to maturation, requiring a myofibroblast-to-fibroblast transition. Cellular decision-making occurs when fibronectin fiber tension switches from highly stretched to relaxed, and it requires the transiently up-regulated appearance of tenascin-C and tissue transglutaminase, matrix metalloprotease activity, as well as a switch from α5β1 to α2β1 integrin engagement and epidermal growth factor receptor signaling. As myofibroblasts are associated with wound healing and inflammatory or fibrotic diseases, crucial knowledge needed to advance regenerative strategies or to counter fibrosis and cancer progression has been gained.

  • Endothelial-Smooth Muscle Cell Interactions in a Shear-Exposed Intimal Hyperplasia on-a-Dish Model to Evaluate Therapeutic Strategies

    Fernandes A., Miéville A., Grob F., Yamashita T., Mehl J., Hosseini V., Emmert M.Y., Falk V., Vogel V.

    Advanced Science （Advanced Science）  9 （ 28 ）  2022年10月

    　概要を見る

    Intimal hyperplasia (IH) represents a major challenge following cardiovascular interventions. While mechanisms are poorly understood, the inefficient preventive methods incentivize the search for novel therapies. A vessel-on-a-dish platform is presented, consisting of direct-contact cocultures with human primary endothelial cells (ECs) and smooth muscle cells (SMCs) exposed to both laminar pulsatile and disturbed flow on an orbital shaker. With contractile SMCs sitting below a confluent EC layer, a model that successfully replicates the architecture of a quiescent vessel wall is created. In the novel IH model, ECs are seeded on synthetic SMCs at low density, mimicking reendothelization after vascular injury. Over 3 days of coculture, ECs transition from a network conformation to confluent 2D islands, as promoted by pulsatile flow, resulting in a “defected” EC monolayer. In defected regions, SMCs incorporated plasma fibronectin into fibers, increased proliferation, and formed multilayers, similarly to IH in vivo. These phenomena are inhibited under confluent EC layers, supporting therapeutic approaches that focus on endothelial regeneration rather than inhibiting proliferation, as illustrated in a proof-of-concept experiment with Paclitaxel. Thus, this in vitro system offers a new tool to study EC-SMC communication in IH pathophysiology, while providing an easy-to-use translational disease model platform for low-cost and high-content therapeutic development.

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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総説・解説等 【 表示 ／ 非表示 】

  • 立体面上で細胞達が生み出す不思議な形

    山下忠紘

    化学と教育 73 （ 1 ） 12 - 15 2025年01月

    記事・総説・解説・論説等（その他）, 筆頭著者, 最終著者, 責任著者

  • 細胞シートの力学: 細胞集団はどのようにして培養足場から剥がれるのか?

    山下忠紘

    細胞 （北隆館）  56 （ 7 ） 31 - 35 2024年05月

    記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）, 単著, 筆頭著者, 最終著者, 責任著者

  • マイクロ構造体上での組織変形を記述する粒子ベース力学モデルの開発

    山下忠紘, 松澤諒介, 松尾瑛, 深町崇耶, Philip Kollmannsberger, 須藤亮, 奥田覚

    化学とマイクロ・ナノシステム 22 （ 1 ） 26 - 29 2023年03月

    記事・総説・解説・論説等（その他）, 共著, 筆頭著者, 責任著者

  • 細胞の「力」を見る

    竹内翠, 山下忠紘

    化学とマイクロ・ナノシステム 20 （ 2 ） 56 - 57 2021年10月

    記事・総説・解説・論説等（その他）, 共著, 最終著者, 責任著者

  • Shaping tissues by balancing active forces and geometric constraints

    Jasper Foolen, Tadahiro Yamashita, Philip Kollmannsberger

    Journal of Physics D: Applied Physics （Institute of Physics）  49 （ 5 ） 053001 2015年12月

    記事・総説・解説・論説等（学術雑誌）, 共著, 筆頭著者

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 曲率を基軸に展開する2次元細胞培養系と3次元細胞培養系の統合的理解

    2024年04月
    -
    2028年03月

    山下 忠紘, 基盤研究(B), 補助金,  研究代表者

  • ポンプレスマイクロ灌流細胞培養デバイスの開発

    2024年04月
    -
    2025年03月

    JKA, 競輪とオートレースの補助事業, 補助金,  未設定

  • 足場曲率と細胞結合リガンドのエンジニアリングによる細胞の表現型制御

    2023年04月
    -
    2025年03月

    山下 忠紘, 学術変革領域研究(A), 補助金,  研究代表者

  • 細胞張力計測に基づく細胞の曲面形状認識・応答挙動の解析

    2021年04月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山下 忠紘, 若手研究, 補助金,  研究代表者

  • マイクロ曲面上でのマイクロピラー張力顕微法の開発

    2021年04月
    -
    2022年03月

    精密測定技術振興財団, 助成金, 補助金,  研究代表者

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受賞 【 表示 ／ 非表示 】

  • ROBOMECH 2023 分野融合研究優秀表彰

    山下忠紘 他, 2024年05月, 日本機械学会 ロボティクス・メカトロニクス部門, 蛍光共鳴エネルギー移動によりひずみを可視化するハイドロゲル

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • Asian-Pacific Conference on Biomechanics 2021 Outstanding Abstract Award

    2021年12月

    受賞区分： 国際学会・会議・シンポジウム等の賞

  • 生体医工学シンポジウム ベストレビューワーアワード

    2021年09月

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • 第4回分子ロボティクス年次大会 若手奨励賞

    2020年11月

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • LIFE2019 若手プレゼンテーション賞

    2019年09月

    受賞区分： 国内学会・会議・シンポジウム等の賞

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担当授業科目 【 表示 ／ 非表示 】

  • システムデザイン工学輪講

    2025年度

  • 環境システム科学

    2025年度

  • 生命システムの物理と化学

    2025年度

  • システムデザイン工学実験第１

    2025年度

  • 理工学基礎実験

    2025年度

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社会活動 【 表示 ／ 非表示 】

  • ハイドロゲルって何だろう？

    川崎市立木月小学校・慶應義塾大学理工学部, ケーキ☆サイエンス（ひらめき☆ときめきサイエンス） （川崎市立木月小学校）

    , 
    2023年10月
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所属学協会 【 表示 ／ 非表示 】

  • 未来医学研究会, 

    2021年
    -
    継続中

  • 日本機械学会, 

    2019年
    -
    継続中

  • 日本生体医工学会, 

    2017年
    -
    継続中

  • 日本化学会, 

    2010年
    -
    継続中

  • 化学とマイクロ・ナノシステム学会, 

    2009年
    -
    継続中
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