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
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経歴 【 表示 ／ 非表示 】

  • 2013年11月
    -
    2018年03月

    ETH Zurich, 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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論文 【 表示 ／ 非表示 】

  • 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.

  • Spatial Heterogeneity of Invading Glioblastoma Cells Regulated by Paracrine Factors

    Chonan Y., Yamashita T., Sampetrean O., Saya H., Sudo R.

    Tissue Engineering - Part A （Tissue Engineering - Part A)  28 （ 13-14 ） 573 - 585 2022年07月

    ISSN  19373341

    　概要を見る

    Glioblastoma (GBM) is the most common and lethal type of malignant primary brain tumor in adults. GBM displays heterogeneous tumor cell population comprising glioma-initiating cells (GICs) with stem cell-like characteristics and differentiated glioma cells. During GBM cell invasion into normal brain tissues, which is the hallmark characteristic of GBM, GICs at the invasion front retain stemness, while cells at the tumor core display cellular differentiation. However, the mechanism of cellular differentiation underlying the formation of spatial cellular heterogeneity in GBM remains unknown. In the present study, we first observed spatially heterogeneous GBM cell populations emerged from an isogenic clonal population of GICs during invasion into a 3D collagen hydrogel in a microfluidic device. Specifically, GICs at the invasion front maintained stemness, while trailing cells displayed astrocytic differentiation. The spatial cellular heterogeneity resulted from the difference in cell density between GICs at the invasion front and trailing cells. Trailing GICs at high cell density exhibited astrocytic differentiation through local accumulation of paracrine factors they secreted, while cells at the invasion front of low cell density retained stemness due to the lack of paracrine factors. In addition, we demonstrated that interstitial flow suppressed astrocytic differentiation of trailing GICs by the clearance of paracrine factors. Our findings suggest that intercellular crosstalk between tumor cells is an essential factor in developing the spatial cellular heterogeneity of GBM cells with various differentiation statuses. It also provides insights into the development of novel therapeutic strategies targeting GBM cells with stem cell characteristics at the invasion front. We elucidated the mechanism of cellular differentiation underlying the spatial cellular heterogeneity of glioblastoma composed of glioma-initiating cells (GICs) and differentiated glioma cells during invasion in a microfluidic device. Trailing cells at high cell density exhibited astrocytic differentiation through local accumulation of paracrine factors they produced, while cells at the invasion front of low cell density were shown to retain stemness due to the lack of paracrine factors. Our findings provide valuable knowledge for the development of effective therapeutic strategies targeting GICs at the invasion front.

  • Control of vessel diameters mediated by flow-induced outward vascular remodeling in vitro

    Sano H., Watanabe M., Yamashita T., Tanishita K., Sudo R.

    Biofabrication （Biofabrication)  12 （ 4 ）  2020年10月

    ISSN  17585082

    　概要を見る

    Vascular networks consist of hierarchical structures of various diameters and are necessary for efficient blood distribution. Recent advances in vascular tissue engineering and bioprinting have allowed us to construct large vessels, such as arteries, small vessels, such as capillaries and microvessels, and intermediate-scale vessels, such as arterioles, individually. However, little is known about the control of vessel diameters between small vessels and intermediate-scale vessels. Here, we focus on vascular remodeling, which creates lasting structural changes in the vessel wall in response to hemodynamic stimuli, to regulate vessel diameters in vitro. The purpose of this study is to control the vessel diameter at an intermediate scale by inducing outward remodeling of microvessels in vitro. Human umbilical vein endothelial cells and mesenchymal stem cells were cocultured in a microfluidic device to construct microvessels, which were then perfused with a culture medium to induce outward vascular remodeling. We successfully constructed vessels with diameters of 40-150 μm in perfusion culture, whereas vessels with diameters of <20 μm were maintained in static culture. We also revealed that the in vitro vascular remodeling was mediated by NO pathways and MMP-9. These findings provide insight into the regulation of diameters of tissue-engineered blood vessels. This is an important step toward the construction of hierarchical vascular networks within biofabricated three-dimensional systems.

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 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

  • マイクロ曲面操作で切り拓く細胞の形状認識機構と接着界面力学のメカノバイオロジー

    2019年04月
    -
    2021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

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受賞 【 表示 ／ 非表示 】

  • 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

    2024年度

  • 生命システムの物理と化学

    2024年度

  • システムデザイン工学実験第１

    2024年度

  • 理工学基礎実験

    2024年度

  • 総合デザイン工学課題研究

    2024年度

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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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