細胞外基質（ECM）在調節細胞生理過程中扮演著關鍵的角色。透過細胞-細胞外基質界面，細胞能夠感應細胞外基質的刺激並啟動細胞內的訊號傳遞路徑。細胞與細胞外基質的相互作用已被廣泛研究，然而，從細胞外基質界面傳遞訊號至整個細胞集體的過程仍不完全瞭解。本研究旨在探討細胞外基質對膠質瘤球體的力學特性和細胞骨架重組的影響，以星狀膠質瘤球體作為多細胞模型系統。研究結果顯示，當膠質瘤球體與膠原蛋白局部的接觸後，球體的剛性顯著增加(~100%），並且在接觸後的數分鐘內就發生。相比之下，與透明質酸（HA）接觸的膠質瘤球體的剛性增加較小（~26%），顯示不同細胞外基質成分引起不同的反應。細胞牽引力顯微鏡觀察顯示，細胞球體與膠原蛋白間的牽引力比在細胞與透明質酸間的牽引力大，說明了細胞球體的剛性與細胞牽引力的正相關性。接著透過免疫螢光染色，發現肌動蛋白絲在細胞球體內的分佈隨時間從球體底部由下往上、由外向內的協調傳播，這表明在細胞球體內存在著協同反應。這些發現強調了細胞球體內部集體力學的感知。最後，透過細胞侵襲實驗，我們觀察到細胞球體僅與膠原蛋白局部接觸即可增強細胞球體的侵襲能力，這除了說明細胞外基質對於細胞球體行為發展的重要影響，也揭示了細胞機械特行的改變會對細胞行為發展產生影響。我們深入探討了細胞球體與細胞外基質之間相互作用的影響，並透過我們的模型揭示了細胞球體內部的機械信號傳感，這對於組織發育、維持穩定以及疾病進展的基本機制至關重要。我們預期這種認識對於再生醫學、組織工程和與細胞外基質相關疾病的研究具有重要意義。

The extracellular matrix (ECM) plays a crucial role in regulating cellular physiology and tumor progression. However, the mechanisms involved in the transmission of mechanical signals within cell collectives, specifically in glioma spheroids, remain unclear. This study aimed to investigate the effects of the ECM on the mechanical properties and cytoskeletal dynamics of glioma spheroids as an in vitro multicellular model system. Nano-indentation measurements showed a significant increase in spheroid stiffness (~100%) upon localized contact with collagen-coated substrates, indicating an immediate cellular response. In contrast, glioma spheroids in contact with hyaluronic acid (HA) exhibited a smaller stiffness increase (~26%), suggesting distinct responses to different ECM components. Cell traction force microscopy revealed higher cellular forces at the cell-collagen interface, which correlated with changes in spheroid stiffness. Confocal microscopy analysis demonstrated a coordinated pattern of cytoskeletal reorganization, propagating from the bottom to the top and from the outer to inner regions of the spheroids. Additionally, we observed that local contact with collagen enhanced the invasive capability of glioma spheroids, underscoring the significant impact of the ECM on the behavior of cellular collectives. These findings provide insights into the influence of the ECM on the mechanical properties and cytoskeletal dynamics of glioma spheroids. Understanding collective mechanosensing in multicellular systems contributes to our knowledge of tumor progression. Future investigations targeting ECM-mediated cellular behavior could lead to innovative therapeutic strategies for tumor control.

摘要 i
Abstract ii
致謝 iii
目錄 iv
圖目錄 vi
表目錄 vii
第一章 緒論 1
1-1. 前言 1
1-2. 研究方法 2
1-3. 本文架構 3
第二章 文獻回顧 4
2-1. 細胞力學 (Cell mechanics) 4
2-2. 三維腫瘤球體 ( 3D tumor spheroids) 5
2-3. 細胞間的連結 (Cell-cell junction) 6
2-4. 細胞外基質(Extracellular matrix, ECM) 7
2-5. 細胞的黏附作用 (Cell adhesions) 9
2-6. 細胞機械訊號傳導 (Cell mechanotransduction) 11
2-6-1. 細胞機械傳感 (Cell mechanosensing) 12
2-6-2. 細胞內的機械訊號傳遞(Cell mechanosignalling) 13
2-6-3. 相關的信號通路(Related signaling pathways) 16
2-7. 機械力的測量方式 (Measuring method of mechanical force) 19
2-8. 研究動機(Motivation) 20
第三章 材料與方法 21
3-1. 實驗材料與設備 21
3-2. 細胞培養 (Cell culture) 23
3-3. 三維細胞球培養 (Spheroid 3D Culture) 23
3-4. 細胞外基質製備與塗層 24
3-4-1. 膠原蛋白(Collagen Ⅰ)製備與塗層 24
3-4-2. 透明質酸(Hyaluronic acid, HA)製備與塗層 24
3-4-3. 膠原蛋白-透明質酸(Collagen-HA)製備與塗層 24
3-5. 3D細胞球體免疫螢光染色( Immunofluorescent staining of 3D cell spheroids) 25
3-6. 聚丙烯醯胺膠 (Polyacrylamide gel) 26
3-6-1. 蓋玻片前處理 26
3-6-2. 聚丙烯醯胺膠成形 26
3-6-3. 細胞外基質塗層 27
3-7. 細胞牽引力顯微鏡 (Traction force microscopy) 28
3-7-1 聚丙烯醯胺膠上嵌入螢光珠粒 28
3-7-2 顯微鏡拍攝 28
3-7-3 數據分析 28
3-8. 奈米壓痕測試 (Nanoindenter) 29
3-8-1. 數據分析 30
3-9. 細胞侵襲測試 (Cell invasion) 30
第四章 結果與討論 31
4-1. 細胞外基質透過局部接觸改變細胞球體的剛性 31
4-2. 膠原蛋白在五分鐘內顯著的提升了細胞球體的剛性 36
4-3. 細胞牽引力與細胞球體的剛性有正相關性 39
4-4. F-肌動蛋白在細胞球體內時空下的分布 43
4-5. 細胞球體內的機械訊號傳感為一個動態的過程 48
4-6. 細胞球體內的機械訊號傳感 51
4-7. 與膠原蛋白局部接觸降低了細胞球體侵襲的強度 62
第五章 結論 65
第六章 未來發展 66
文獻參考 67

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