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研究生： 劉原安
Liu, Yuan-An
論文名稱： 人體腸道組織之三維影像研究
Three-Dimensional Histology of Human Intestinal Tissue Network
指導教授： 湯學成
Tang, Shiue-Cheng
口試委員: 湯學成
陳令儀
鍾元強
連吉時
潘憲棠
學位類別： 博士
Doctor
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2014
畢業學年度： 102
語文別： 英文
論文頁數： 129
中文關鍵詞： 腸道組織 、三維影像 、光學澄清 、組織學
外文關鍵詞： Enteric nervous system, intestine
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    • 人體腸道組織中網路系統的顯微影像在疾病的診斷上扮演著重要的角色。然而由於網路系統，如神經與血管網路，分散在三維的空間中，傳統的二維組織切片影像無法提供足夠的影像資訊。為了得到網路系統的三維影像，我們利用光學澄清技術增加組織的透光度，並利用共軛焦顯微鏡取得厚組織的三維影像。利用三維影像的資料，我們發展了定性與定量的分析方法，作為判斷腸道組織中網路系統健全與否的工具。
    本研究使用的組織來自手術摘除的人體腸道組織，包括正常以及疾病的部分。利用免疫染色技術呈現組織的微結構以及網路系統。接著利用光學澄清技術將染色後的組織透明化，使得共軛焦顯微鏡可取得深度300微米的連續組織切片影像。最後利用三維影像處理軟體重組成三維影像，同時進行影像去雜訊、選取、投影以及各種定量分析。
    光學澄清大幅降低了光訊號的散射，使得我們可以觀察到更深處的組織影像且維特良好的訊號與雜訊比。發揮這樣的優勢，我們分別建構腸道肌肉層與黏膜層中的三維神經與血管網路，同時觀察神經以及血管等網路組織在空間中的交互關係。除此之外，藉由相同的影像方法，我們也建構了腸道肌肉層中的三維ICC網路，並呈現他們在不同肌肉層中的形貌。
    除了呈現正常組織中的三維網路，在本研究中，我們也觀察到血管與膠質細胞網路在大腸癌組織中的改變。相對於正常的大腸組織，我們觀察到形貌與定量上，如細胞數量、密度，的變化情形。
    最後，本研究使用的三維影像工具可用來觀察網路系統間的空間關係，並藉此證實或推測他們之間的生理功能。本研究觀察ICC與血管網路的空間分佈，發現一部分的ICC與微血管緊密地接觸。根據空間中ICC與微血管的接觸情形，我們提出了新的ICC分類: Peri-capillary ICC.
    總結來說，我們發展一套三維組織影像的方法用來觀察人體腸道中的網路組織影像。結合形貌上與定量的分析工具，這套三維組織影像的方法可以為將來腸道組織的生理以及病理研究建立良好的基礎。

    Microscopic examination of intestinal neurovascular tissues is a valuable diagnostic tool to evaluate intestinal diseases. However, the standard microtome-based 2-dimensional histology provides only limited perspective of the dispersed intestinal tissue network in space. To provide a global view of the network structure, in this research we employed optical clearing to generate transparent tissue specimens for penetrative 3-dimensional (3-D) visualization of the intestinal architecture. Qualitative and quantitative analyses were developed to characterize the 3-D intestinal networks in health and disease.
    In this thesis we acquired the human intestinal tissues from surgical resection for intestinal diseases. Both normal and diseased tissues were included in analysis. Nuclear and immunostaining of the tissue specimens were employed to reveal the intestinal microstructure and tissue networks. Afterward, optical clearing was used to generate transparent intestinal specimens, which led to panoramic visualization of the tissue networks up to 300 μm in depth via confocal microscopy with subcellular resolution. Spatial projection, analysis and quantitation were performed using the 3-D analytical software Avizo.
    Significantly, preparation of transparent human intestinal specimens by optical clearing led to less fluorescence signal decay in confocal microscopy, achieving higher signal-to-noise ratio of the acquired images (Chapter B). The 3-D vascular and innervation patterns in association with their microstructures were constructed at both the intestinal mucosa and wall. In addition to the neurovascular structure, in colon microscopy we also acquired the 3-D structure of the interstitial cells of Cajal (ICC) to delineate their morphological patterns (Chapter C).
    For the diseased tissues, in this thesis we examined the vasculature and glial network in colorectal carcinoma and differentiate their morphological and quantitative differences in comparison with those in the normal human colon mucosa (Chapter D and E).
    Finally, to analyze the association between the intestinal tissue networks, we examined the association of ICC with the microvascular network in the human colon wall via high-definition 3-D microscopy. A new subclass of ICC, the peri-capillary ICC, is proposed and qualitatively and quantitatively characterized to highlight this unique cell population (Chapter F).
    In sum, the microscopic and illustration methods/approaches developed in this research highlight the technical advance in 3-D gastrointestinal histology. The morphological and quantitative information of the intestinal tissue networks will lay the foundation for future study of the intestinal physiology and pathophysiology.

    Table of Contents List of Figures vii List of Tables ix Abstract x 中文摘要 xii Chaper A : Background 1 A.1. Network systems in intestinal tissue 1 A.1.1. Histology of the gastrointestinal tract 1 A.1.2. Enteric nervous system 2 A.1.3. Interstitial cells of Cajal 3 A.1.4. Vasculature 4 A.2. Imaging strategies to reveal intestinal network systems 4 A.2.1. Immunostaining 4 A.2.2. Optical clearing 4 A.2.3. Confocal microscopy 5 Chaper B : Optical Clearing Improves the Imaging Depth and Signal-to-noise Ratio for Digital Analysis and Three-dimensional Projection 6 B.1. Abstract 6 B.2. Introduction 6 B.3. Materials and methods 8 B.3.1. Human specimens 8 B.3.2. Immunostaining 9 B.3.3. Confocal microscopy 9 B.3.4. Image analysis, processing, and projection 10 B.4. Results 10 B.4.1. Optical clearing of the human ileal wall 10 B.4.2. Optical clearing increases the imaging depth in neurohistology 11 B.4.3. Software-based signal analysis of the nerve fibers in the muscle layer 12 B.4.4. Noises caused by tissue opacity interfere with nerve fiber detection 12 B.4.5. Optical clearing facilitates software-based signal processing and analysis of the nerve fibers 13 B.4.6. Panoramic visualization of the enteric plexus and related elements 14 B.5. Discussion 15 Chaper C : 3-D Illustration of Network Orientations of Interstitial Cells of Cajal Subgroups in Human Colon as Revealed by Deep-tissue Imaging with Optical Clearing 26 C.1. Abstract 26 C.2. Introduction 27 C.3. Material and methods 28 C.3.1. Human specimens 28 C.3.2. Tissue labeling 29 C.3.3. Confocal microscopy 29 C.3.4. Image processing and projection 30 C.4. Results 31 C.4.1. Deep-tissue microscopy of ICC with optical clearing 31 C.4.2. Periganglionic ICC-MY joint with ICC-LM and ICC-CM 32 C.4.3. ICC-LM within the longitudinal muscle 32 C.4.4. 3-D orientation of the repetitive and organized ICC-CM network 33 C.4.5. ICC-SM layer lining the submucosal boundary 34 C.4.6. Quantitative analysis of ICC density 34 C.4.7. Exclusion of mast cells and identification of septal ICC using in-depth image projection 35 C.5. Discussion 36 Chaper D : 3-D Visualization and Quantitation of Microvessels in Transparent Human Colorectal Carcinoma 49 D.1. Abstract 49 D.2. Introduction 50 D.3. Materials and methods 51 D.3.1. Human specimens 51 D.3.2. Tissue labeling 52 D.3.3. Confocal microscopy 52 D.3.4. Imaging processing and projection 53 D.4. Results 53 D.4.1. Optical clearing of human colon mucosa and colorectal carcinoma 53 D.4.2. Optical clearing enables deep-tissue vascular microscopy 54 D.4.3. Panoramic visualization of colonic microstructure and vasculature 54 D.4.4. Matched tissue information in 3-D and 2-D histology 55 D.4.5. 3-D imaging and illustration of microvasculature in adenocarcinoma 56 D.4.6. Quantitation of spatial microvessel density 57 D.5. Discussion 58 Chaper E : 3-D Imaging, Illustration, and Quantitation of Enteric Glial Network in Transparent Human Colon Mucosa 71 E.1. Abstract 71 E.2. Introduction 71 E.3. Material and Methods 74 E.3.1. Human specimens 74 E.3.2. Tissue labeling 75 E.3.3. Confocal microscopy 76 E.3.4. Image processing, projection, and analysis 77 E.4. Results 78 E.4.1. Optical clearing facilitates photon penetration for in-depth imaging of colon mucosa 78 E.4.2. Transparent mucosa shows peri-vascular and peri-cryptic morphologies of the glial network 78 E.4.3. A dense glial population lining the crypt base/ mucosal boundary in contact with lymphatic vessels 79 E.4.4. Quantitative analysis of the location-dependent glial cell density 80 E.4.5. Irregular crypts in adenoma lack peri-cryptic glial fibers 81 E.5. Discussion 82 Chaper F : Peri-capillary interstitial cells of Cajal in human colon 94 F.1. Abstract 94 F.2. Introduction 95 F.3. Materials and methods 97 F.3.1. Human specimens 97 F.3.2. Tissue labeling 97 F.3.3. Confocal microscopy 98 F.3.4. Image processing and projection 98 F.3.5. Image analysis 99 F.3.6. Statistical analysis 99 F.4. Results 99 F.4.1. Deep-tissue microscopy of ICC and vascular networks 99 F.4.2. Peri-capillary ICC in the ICC-SM and ICC-MY populations 100 F.4.3. Peri-capillary ICC in longitudinal muscle 100 F.4.4. Peri-capillary ICC in circular muscle 101 F.4.5. Type I peri-capillary ICC in clusters and with elevated c-kit staining levels 102 F.4.6. Peri-capillary ICC in the ICC-CM network 102 F.5. Discussion 103 Chaper G : Whole-villus Neurohistology with Optical Clearing 113 G.1. Abstract 113 Chaper H : Conclusion and Future Work 117 References 119 Appendix 128

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