利用新式三維細胞培養系統研究癌症與組織工程中異種細胞間交互作用

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研究生：	林叡增 Ruei-Zeng Lin
論文名稱：	利用新式三維細胞培養系統研究癌症與組織工程中異種細胞間交互作用 Studies of Heterogeneous Cell-Cell Interactions in Cancer Biology and Tissue Engineering Using Novel Three-dimensional Cell Culture Models
指導教授：	張晃猷 Hwan-You Chang
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2007
畢業學年度：	96
語文別：	英文
論文頁數：	173
中文關鍵詞：	細胞球體、組織工程、介電泳、轉移、活性氧
相關次數：	點閱：3 下載：0
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與傳統二維平面細胞培養系統相比，新式的三維細胞培養方式能提供更接近真實組織的環境，並引導細胞表現出更真實的細胞-基質或細胞-細胞間交互作用。因此，對於未來生物醫學研究上，選用能適當代表體內環境的三維細胞培養便顯得越來越重要。在各類三維細胞培養系統中，最常被使用的是細胞球體技術。細胞球體是由數百至數千顆懸浮細胞團聚所形成的三維球形細胞團，在細胞球體中，各個細胞被其他細胞與細胞外間質所包圍，並發展出組織特異性的細胞形態與結構。在本論文中，我們首先探討細胞球體形成的分子機制，並鑑定出細胞聚集成球體須經過integrin與cadherin等細胞黏附因子參與的兩階段細胞交互作用。我們也發展出新式的細胞球體培養技術，包括將微米磁珠標定於細胞球體內，並用磁力來控制並排列細胞球體。此外也發展能讓血管內皮細胞與肝細胞ㄧ同形成異質細胞球體的技術，並應用於血管化組織工程上。本文中亦探討利用介電泳力排列細胞的可行性，並成功發展出能排列肝組織與骨組織的介電泳生物晶片。最後，我們亦利用上述的三維細胞培養系統來探討癌症轉移時，癌細胞與血管內皮細胞的交互作用，並發現癌細胞可以透過活化內皮細胞內活性氧分子的大量產生，來促使局部區域血管細胞的細胞凋亡與血管壁破損，進而方便癌細胞從血管中穿出，達成轉移的作用。在三維細胞培養越來越受重視的今天，本文所發展的各種技術將可提供給生物醫學界更多的選擇，並更真實的貼近組織中細胞行為，以取得更可信的研究成果。

In comparison with conventional monolayer cultures, which are unable to generate normal cell-cell interactions found in vivo, cells grown in three-dimensional (3D) environments more closely resemble the situation in real tissues with regard to differentiation patterns and cell-cell and cell-extracellular matrix interactions. In addition, similarities in gene expression, cell behavior, and ultrastructures between 3D cells in culture and in vivo tissues also reveal the potential as models to mimic actual situation in our body. The multicellular spheroidal organoids (spheroids), aggregated from hundreds to thousands of suspended cells, have been exploited widely as the convenient 3D culture models. In this thesis, we first clarified the molecular mechanism involved in the formation of spheroids and identified the roles of integrin and cadherin in the cellular self-assembly process. To extend the applications of spheroid-based 3D culture systems, we also developed novel techniques to manipulate magnetic particle-labeled spheroids to form designed patterns. Furthermore, a new strategy to vascularize engineered thick tissues using heterospheroids was also proposed and demonstrated in an artificial liver system. For certain applications that require high-resolution cellular organizations to study cell-cell interactions, the dielectrophoresis-based cell patterning technique was investigated for efficiency of liver and bone pattern formation with high cell viability and adhesion. Finally, we studied the cell-cell interactions contributing to the critical step of tumor metastaisis − extravasation, by which circulating tumor cells migrate through damaged endothelial barriers. We proposed a model that the contact of tumor and endothelium will induce apoptosis of endothelial cells through ROS-mediated cytotoxicity. The NADPH oxidase was identified as the main source of ROS generation in responding to tumor induction. These data provide a molecular basis to explain how anti-oxidant administration may inhibit tumor metastasis. In summary, we believe that the studies presented in this thesis will greatly contribute to our knowledge on spheroid self-assembly process and efficient generation of the spheroid-based 3D cell culture to meet the increasing demands for 3D cell models in biomedical researches.

Abstract (English) ………………………………………………………………………………...    I
Abstract (Chinese) ………………………………………………………………………………...    III
Abbreviations ……………………………………………………………………………………..    IV
Acknowledgement ………………………………………………………………………………...    V
Table of contents …………………………………………………………………………………..    VI
Table of figures ……………………………………………………………………………………    XI
Table of tables ……………………………………………………………………………………..    XIII

Chapter 1: General introduction
1 The significance of 3D cell culture systems ……………………………………………………    2
2 Current status of 3D cell culture models ……………………………………………………….    3
3 Spheroids as models for cancer biology ……………………………………………………….    6
4 Spheroids as tools for tissue engineering ………………………………………………………    6
5 The limitations of current spheroid systems …………………………………………………...    7
6 Conclusion ……………………………………………………………………………………..    9

Chapter 2: Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and □1-integrin
1 Abstract ………………………………………………………………………………………...    11
2 Introduction ……………………………………………………………………………………    12
3 Materials and methods …………………………………………………………………………    14
3.1 Cell lines and growth conditions …………………………………………………………    14
3.2 Generation of spheroids ………………………………………………………………….    14
3.3 Quantification of spheroid compactness …………………………………………………    15
3.4 Reverse-transcription and real-time PCR ………………………………………………..    16
3.5 Quantification of ECM proteins secreted from cells …………………………………….    18
3.6 Determination of permeability of spheroids to small molecules ………………………...    19
3.7 Effects of ECM, integrin, and E-cadherin activities on spheroid formation …………….    19
4 Results ………………………………………………………………………………………….    21
4.1 Quantification of shrinkage rates of cell aggregates in spheroid formation ……………..    21
4.2 Dynamic analysis of spheroid formation in three hepatoma cell lines …………………..    22
4.3 Differential expression of cadherins in hepatoma cell lines ……………………………..    24
4.4 Secretion of ECM by different hepatoma cells …………………………………………..    24
4.5 Effects of ECM on spheroid formation …………………………………………………..    25
4.6 Three distinct stages of spheroid formation in PLC/PRF/5 and HepG2 cells ……………    26
4.7 Permeability and morphology of cell aggregates at different spheroid assembly stages ...    28
4.8 Participation of integrins and ECM in rapid cell aggregation ……………………………    30
4.9 Roles of E-cadherin in the development of compact spheroids from loose aggregates ….    32
4.10 Participation of integrins in the early stages of spheroid formation ……………………    32
4.11 E-cadherin is required for the compact assembly stage of spheroid formation ………...    33
4.12 Expression of E-cadherin gene during spheroid formation …………………………….    33
4.13 Model of spheroid formation …………………………………………………………...    34
5 Discussion ……………………………………………………………………………………...    37
6 Conclusion ……………………………………………………………………………………..    40

Chapter 3: Manipulation and micropatterning of multicellular spheroids with magnetic force
1 Abstract ………………………………………………………………………………………...    42
2 Introduction …………………………………………………………………………………….    43
3 Materials and methods …………………………………………………………………………    45
3.1 Synthesis of RGD-conjugated MPs ……………………………………………………...    45
3.2 Cells and culture conditions ……………………………………………………………..    45
3.3 Generation of MP-labeled spheroids …………………………………………………….    46
3.4 Quantification of spheroid compactness …………………………………………………    46
3.5 Manipulation of spheroids by magnetic probes ………………………………………….    46
3.6 Spheroid patterning by magnetic force …………………………………………………..    47
3.7 Titration of MP numbers required for efficient manipulation ……………………………    47
3.8 Determination of cellular physiology …………………………………………………….    48
3.9 Immobilization of spheroid patterns in hydrogels ……………………………………….    48
4 Results ………………………………………………………………………………………….    50
4.1 Magnetically labeling spheroids with RGD-conjugated MPs ……………………………    50
4.2 Manipulation of spheroids by magnetic force ……………………………………………    52
4.3 Magnetically micropatterning of spheroids ……………………………………………...    54
4.4 The number of MPs packed into spheroids determines the MOP efficiency …………….    57
4.5 RGD-MPs does not affect cell physiology ……………………………………………….    57
4.6 Growth of spheroid patterns in ECM gels ………………………………………………..    59
4.7 Generation of engineered liver tissue constructs with vascular networks ……………….    61
4.8 Reconstruction of multi-layered 3D tissues by Mebiol gel ………………………………    63
4.9 Patterned spheroids in photocrosslinked PEG microchannels …………………………...    64
5 Discussion ……………………………………………………………………………………...    67

Chapter 4: Vascularized Liver Tissue Engineering via self-assembly hepatic-endothelial organoids
1 Abstract ………………………………………………………………………………………...    69
2 Introduction …………………………………………………………………………………….    70
3 Materials and methods …………………………………………………………………………    72
3.1 Hepatocyte isolation and culture …………………………………………………………    72
3.2 Endothelial cell isolation and culture …………………………………………………….    72
3.3 Hepatocyte spheroids formation …………………………………………………………    73
3.4 Generation of hepatic-endothelial hetero-spheroids ……………………………………..    73
3.5 Spheroid morphology …………………………………………………………………….    74
3.6 Immunohistochemical analysis …………………………………………………………..    74
3.7 Embedded hetero-spheroids in collagen gels …………………………………………….    74
4 Results ………………………………………………………………………………………….    75
4.1 ECs failed to invade primary hepatocyte spheroids ……………………………………...    75
4.2 New strategy for microtissue neovascularization ………………………………………..    76
4.3 Self-assembly of hepatic-endothelial heterospheroids …………………………………..    77
4.4 ECM and □1-integrin mediated the assembly of heterospheroids ……………………….    78
4.5 Improved cell viability and liver functions in heterospheroids …………………………..    80
4.6 Establishment of cell polarity in heterospheroids ………………………………………..    81
4.7 Vascular networks interconnecting several heterospheroids in collagen gels…………….    82
5 Discussion ……………………………………………………………………………………...    84

Chapter 5: Rapid heterogeneous cell on-chip patterning via the enhanced field-induced dielectrophoresis trap
1 Abstract ………………………………………………………………………………………...    86
2 Introduction …………………………………………………………………………………….    87
3 Principle of dielectrophoresis …………………………………………......................................    90
4 Chip Designs - Electrode geometry for cell patterning ………………………………………...    93
5 Microfabrication process ……………………………………………………………………….    95
6 Materials and methods …………………………………………………………………………    97
6.1 Cell culture and media …………………………………………………………………...    97
6.2 Cell preparation for DEP manipulation ………………………………………………….    97
6.3 Preparation of HA-PLGA Microparticles ………………………………………………..    97
6.4 Synthesis of diacrylate PEG ……………………………………………………………..    98
6.5 Synthesis of PLA-b-PEG-b-PLA-diacrylate copolymer …………………………………    99
6.6 Experimental setup for cell-patterning experiments ……………………………………..    100
6.7 DEP cell-patterning ………………………………………………………………………    101
7 Results ………………………………………………………………………………………….    103
7.1 On-chip in-parallel cell-patterning demonstration ……………………………………….    103
7.2 In-situ cell-viability assessment for DEP cell patterning ………………………………...    106
7.3 Enhancement of cell adhesion via collagen coating and medium replacement ………….    107
7.4 Patterned liver and endothelial cells by horizontal p-DEP to mimic hepatic tissues …….    109
7.5 Vertical p-DEP for large-area liver tissue formation ……………………………………..    112
7.6 Cell patterning mimicking bone tissues using hybrid DEP manipulation ……………….    114
8 Discussion and conclusion……………………………………………………………………...    117
Chapter 6: Tumor-induced endothelial cell apoptosis: roles of NADPH oxidase-derived reactive oxygen species
1 Abstract ………………………………………………………………………………………...    124
2 Introduction …………………………………………………………………………………….    125
3 Materials and methods …………………………………………………………………………    127
3.1 Reagents, inhibitors and antibodies ………………………………………………………    127
3.2 Cell isolation and culture ………………………………………………………………...    127
3.3 Co-cultivation of EC and tumor cells ……………………………………………………    127
3.4 Determination of cell survival rate in tumor-EC co-culture ……………………………..    128
3.5 Quantification of apoptosis ………………………………………………………………    128
3.6 Detection of intracellular ROS production ………………………………………………    129
3.7 Determination of intracellular O2–• level ([O2–•]i) ………………………………………..    129
3.8 Determination of intracellular NO concentration ([NO]i) ………………………………..    129
3.9 Inhibition of intracellular ROS production ………………………………………………    130
3.10 Preparation of tumor cell aggregates for local tumor-EC interaction …………………..    130
3.11 Detection of PKC□ phosphorylation by western blotting ………………………………    131
3.12 Immunoprecipitation and detection of p47phox phosphorylation ………………………..    131
3.13 Transendothelium migration assay ……………………………………………………..    131
3.14 EC monolayer permeability assay ………………………………………………………    132
3.15 Statistical analysis ………………………………………………………………………    132
4 Results ………………………………………………………………………………………….    133
4.1 HeLa and HepG2 cells induced EC death in co-culture …………………………………    133
4.2 Only solid tumor cells exhibited the killing effects ……………………………………...    135
4.3 The EC apoptosis required contacts between tumor and the ECs ……………………….    135
4.4 Contact with cancer cells induced a rapid increase of intracellular ROS level in ECs …..    136
4.5 Contact with cancer cells induced a rapid increase of [O2–•]i in ECs …………………….    138
4.6 Tumor cells mediated-EC superoxide production was through activation of endothelial
 NADPH oxidase …………………………………………………………………………    140
4.7 Tumor activates endothelial NADPH oxidase through direct cell-cell interaction ………    141
4.8 Tumor cells activate endothelial NADPH oxidase through provoking intra-endothelial
 Ca2+ ………………………………………………………………………………………    143
4.9 Contacting with tumor cells induces phosphorylation of PKC□□and p47phox in HUVECs    143
4.10 Tumor-contact affects endothelial [NO] i………………………………………………..    144
4.11 Inhibition of endothelial NADPH oxidase reduced tumor-induced EC apoptosis ……..    147
4.12 Inhibition of endothelial NADPH oxidase reduced tumor transendothelial migration …    148
4.13 Tumor cells mediated-endothelial barrier dysfunction was not affected by NADPH
 oxidase inhibitors ………………………………………………………………………    149
5 Discussion ……………………………………………………………………………………...    150

Chapter 7: Conclusions and Future Perspectives    155

References …………………………………………………………………………………………    159
List of publications ……………………………………………………………………………….    173
Appendix – A review of spheroid generating techniques ……………………………………….    A1
A1. Non-adhesive surface ………………………………………………………………………….    A1
A2. Large-scale spheroid production in rotary bioreactors ………………………………………..    A2
A3. Hanging drop cultures …………………………………………………………………………    A3
A4. Microfabricated microstructures ………………………………………………………………    A5
A5. Surface-modified substrates or scaffolds ……………………………………………………...    A5
A6. Other spheroid forming techniques ……………………………………………………………    A6

                                

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