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研究生：	李婉寧 Li, Wan-Ning
論文名稱：	探討子宮內膜異位症中淋巴管新生之分子機制 Investigating the molecular mechanism involved in the lymphangiogenesis of endometriosis
指導教授：	蔡少正 Tsai, Shaw-Jenq
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	111
中文關鍵詞：	子宮內膜異位症、血管內皮新生因子C 、雞卵蛋白上游啟動子轉錄因子-II 、細胞外囊泡、介白素17 、淋巴管新生
外文關鍵詞：	Endometriosis, VEGF-C, COUP-TFII, EV, IL-17, lymphangiogenesis
相關次數：	點閱：88 下載：0
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子宮內膜異位症為一慢性發炎婦科疾病，主要在病人體內發現於子宮以外處有子宮內膜組織異常增生的現象。由於疾病發生的病理機制尚未釐清，至今並未有方法能夠根治子宮內膜異位症。在我博士論文的研究中發現，患有子宮內膜異位症的病人中，異位組織和腹腔液中皆有高度表達的血管內皮新生因子C (VEGF-C)，而血管內皮新生因子C為一已知參與在淋巴管新生的主要因子。透過生物資訊分析我們內部 (in-house) 核苷核酸 (RNA) 微陣列 (microarray) 預測，發現雞卵蛋白上游啟動子轉錄因子-II (COUP-TFII) 能夠負調控血管內皮新生因子C。經由一系列細胞以及分生實驗的驗證，我們不只證實血管內皮新生因子C的高度表達確實是來自於促發炎因子抑制雞卵蛋白上游啟動子轉錄因子-II在轉錄上不正常調控所導致，更發現血管內皮新生因子C的釋放是透過細胞外囊泡 (Extracellular vesicle; EV) 運輸的方式傳送到細胞外。除此之外，我們更利用各項體外以及體內的實驗證明血管內皮新生因子C能促進子宮內膜異位症模式裡淋巴管新生的活動性，終致組織中淋巴球細胞的浸潤增加。接下來，我們便進一步探討這些淋巴球細胞參與在疾病中的病理機轉，發現其中輔助型T細胞17 (T helper 17 cells)能夠透過影響異位細胞的白介素-17 (Interleukin-17)相關訊息傳遞來調控子宮內膜組織細胞爬行以及神經生長的能力。已知細胞外囊泡廣布於人體血液以及體液中，因此我們評估透過血清中細胞外囊泡所運輸的血管內皮新生因子C是否能有作為臨床診斷之生物標記的可能性。透過分離病人血清中細胞外囊泡，證實患有子宮內膜異位症的病人含有較高表達的血管內皮新生因子C。整體而言，我們的研究發現了血管內皮新生因子C在子宮內膜異位症中的調控機制，並且證實細胞外囊泡運輸之血管內皮新生因子C在未來診斷病人上是具有潛力的生物標記。

Endometriosis is a chronic inflammatory gynecological disease characterized as the presence of endometriotic lesions outside of the uterine cavity. Owing to unclarified etiology, no treatment could thoroughly cure the disease. Herein, we found vascular endothelial growth factor-C (VEGF-C), a potent lymphangiogenic factor, is upregulated in both endometriotic tissues and peritoneal fluids from patients with endometriosis. Bioinformatic analysis revealed that VEGF-C is negatively regulated by chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), which is an orphan nuclear receptor that modulates a number of vital biological processes. We therefore conducted a series of cellular and molecular studies to reveal the pathophysiological roles of COUP-TFII in endometriosis. Results obtained not only demonstrated that pro-inflammatory cytokines-reduced COUP-TFII could promote the expression of VEGF-C via transcriptional regulation, but also showed that functional VEGF-C is transported out of cells by extracellular vesicles (EV). Both in vitro and in vivo studies indicated that EV-associated VEGF-C enhances tissue lymphangiogenesis, and this is considered a way to provide the route for immune cells recruitment. Furthermore, T helper 17 cells and interleukin-17 (IL-17) signaling are critically involved in promoting cell migration of endometriotic stromal cells and tissue innervation in endometriotic lesions. We have isolated the EV from the sera of both patients with and without endometriosis to evaluate whether EV-associated VEGF-C can be a potential biomarker for clinical diagnosis. The results indicated that EV-associated VEGF-C in sera was significantly higher in patients with endometriosis than in those without. Taken together, we have demonstrated a major regulatory mechanism of VEGF-C production in endometriosis and the potential of using EV-associated VEGF-C in patients’ sera as an indicator for endometriosis.

論文合格證明書	ii
中文摘要	iii
Abstract (English)	iv
誌謝	v
Table of contents	vii
List of figures	x
I. Background	1
1.1 Endometriosis and the etiology	1
1.2 Chronic inflammation and endometriosis	2
1.3 Lymphatic system in endometriosis	3
1.4 COUP-TFII and its role in endometriosis	4
1.5 The pathological role of tissue-infiltrated immune cells in endometriosis	5
1.6 Role of Th17 cells and interleukin (IL)-17 in endometriosis	6
1.7 Extracellular vesicle (EV) and its potent role in causing disease pathogenesis	8
II. Objective and specific aims	10
2.1 Aim 1: To investigate the regulatory role of COUP-TFII involved in the lymphangiogenesis of endometriosis	10
2.2 Aim 2: To characterize the effects of EV in the pathogenesis of endometriosis	10
2.3 Aim 3: To elucidate whether VEGE-C signaling is critical for the pathogenesis of endometriosis in the mice model	11
2.4 Aim 4: To study the pathological role of infiltrated immune cells in endometriosis	12
2.5 Aim 5: To evaluate the potential of using EV-associated VEGF-C for future clinical application	13
III. Materials and Methods	14
3.1 Ethical approval and Clinical samples from patients	14
3.2 Primary stromal cells and cell culture condition	14
3.3 Cell treatments	15
3.4 Microarray data mining and Gene Set Enrichment Analysis (GSEA)	15
3.5 Constructs, small interfering RNA, and transfection	15
3.6 RNA isolation, quantitative reverse transcriptase PCR (RT-qPCR)	16
3.7 Western blotting	16
3.8 Chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR)	17
3.9 Tube formation assay	17
3.10 Transwell migration assay	17
3.11 Cell proliferation assay	18
3.12 EV extraction from cultured conditioned medium and nanoparticle tracing analysis	18
3.13 Tracking EV uptake	19
3.14 Murine model of endometriosis	19
3.15 Immunohistochemistry staining (IHC) and Immunofluorescence staining	20
3.16 EV isolation from serum by size exclusion chromatography (SEC)	20
3.17 Enzyme‐linked immunosorbent assay (ELISA)	21
3.18 Transmission electron microscope examination of immunogold-stained VEGF-C	21
3.19 Statistical analysis	21
IV. Results	22
4.1 Elevation of VEGF-C in endometriosis is mediated by downregulation of COUP-TFII	22
4.1.1 Expression of VEGF-C in endometriosis	22
4.1.2 Expression of COUP-TFII and its correlation with VEGF-C in endometriosis	22
4.1.3 Role of COUP-TFII in regulating VEGF-C expression in endometriosis	23
4.2 Expression of VEGF-C is induced by proinflammatory cytokines-mediated COUP-TFII downregulation	23
4.2.1 The effect of pro-inflammatory cytokines on COUP-TFII and VEGF-C in endometriotic stromal cells	23
4.2.2 Proinflammatory cytokines-suppressed COUP-TFII mediates gene expression in transcriptional level	24
4.3 Suppression of COUP-TFII promotes the secretion of EV-associated VEGF-C further enhancing lymphangiogenesis	24
4.3.1 COUP-TFII knockdown in endometrial stromal cells stimulates tube formation of lymphatic endothelial cells	24
4.3.2 Endometriotic stromal cells release high level of EV	25
4.3.3 Endometriotic stromal cells-secreted VEGF-C is carried by EV	25
4.3.4 EV-associated VEGF-C stimulates lymphatic vessel development	26
4.4 Increased lymphatic vessel and leukocytes infiltration in endometriotic lesion are mediated by VEGF-C	26
4.4.1 Blockage of VEGF-C signaling interferes the growth of endometriotic lesions in mice	26
4.4.2 Enlarged pelvic lymph nodes are related to the active lymphangiogenesis around endometriotic lesions	27
4.4.3 Inhibition of VEGF-C signaling prevents immune cells infiltration in endometriotic lesions	27
4.5 Infiltrated Th17 cells in endometriotic tissues are critically involved in the pathogenesis of endometriosis.	28
4.5.1 Th17 cells are highly infiltrated in DIE tissues	28
4.5.2 IL-17 signaling is dysregulated in endometriotic lesions	29
4.5.3 Aberrant IL-17 signaling may be associated with enhanced cellular migration ability and neural innervation	29
4.6 High clinical relevance of VEGF-C in endometriosis is applicable for future diagnosis	30
4.6.1 Increased immune cells infiltration in endometriotic lesions	30
4.6.2 EV-associated VEGF-C in patient’s serum is a potential diagnostic biomarker	31
V. Discussion	32
VI. References	38
VII. Figures	48
VIII. Tables	103
Table 1: Endometriosis patients' information in the present study	103
Table 2: Primer sequences	108
Table 3: Information about Antibodies & Reagents	109
IX. Publications	111


List of figures
Figure 1 VEGF-C expressed higher in endometriosis.	48
Figure 2 Endometriotic lesions showed higher VEGF-C than normal endometrium.	49
Figure 3 Higher Level of VEGF-C was found in peritoneal fluid of women with endometriosis..	50
Figure 4 Bioinformatics analysis reveals the negative correlation between COUP-TFII and VEGF-C in endometriotic stromal cells.	51
Figure 5 Expression of COUP-TFII showed inverse pattern to that of VEGF-C in endometriotic stromal cells.	52
Figure 6 Repression of COUP-TFII increased VEGF-C expression in endometriotic stromal cells.	53
Figure 7 COUP-TFII overexpression decreased VEGF-C secretion in endometriotic stromal cells..	54
Figure 8 Proinflammatory cytokines suppress COUP-TFII and induce VEGF-C expression.	55
Figure 9 The increase of VEGF-C secretion is mediated by proinflammatory cytokines-suppressed COUP-TFII.	56
Figure 10 COUP-TFII mediates the expression of VEGF-C at the transcriptional level.	57
Figure 11 ChIP analysis also demonstrated that COUP-TFII mediates the expression of VEGF-C at the transcriptional level.	58
Figure 12 Knockdown of COUP-TFII stimulates lymphatic endothelial cell tube formation.	59
Figure 13 Knockdown of COUP-TFII stimulates lymphatic endothelial cell tube formation via VEGF-C-VEGFR signaling..	60
Figure 14 VEGF-C promotes cell proliferation and migration in lymphatic endothelial cells.	61
Figure 15 Endometriotic stromal cells release more nanoparticles than endometrial stromal cells.	62
Figure 16 Endometriotic stromal cells release more EV.	63
Figure 17 Endometriotic stromal cells release EV with more VEGF-C protein.	64
Figure 18 COUP-TFII directly regulates EV-associated VEGF-C secretion from endometriotic stromal cells.	65
Figure 19 Nanoparticles release from endometriotic stromal cells is not directly regulated by proinflammatory cytokines-mediated COUP-TFII.	66
Figure 20 EV derived from endometriotic stromal cells can be uptake by lymphatic endothelial cells.	67
Figure 21 Endometriotic stromal cells-associated VEGF-C promotes tube formation in lymphatic endothelial cells.	68
Figure 22 Extracellular vesicles-associated VEGF-C promotes cell migration in lymphatic endothelial cells..	69
Figure 23 Schematic drawing illustrates the experimental setting of mouse model of endometriosis.	70
Figure 24 Treatment with lenvatinib does not cause adverse effects on mouse..	71
Figure 25 Endometriosis-like mice showed severe adhesion in peritoneum and larger size of endometriotic lesions..	72
Figure 26 VEGF-C enhances endometriotic lesions growth in mice.	73
Figure 27 Lenvatinib suppressed lymphatic system development in endometriotic tissues.	74
Figure 28 Expression level of CD31 is not inhibited by the effect of lenvatinib in mice model..	75
Figure 29 Mice with surgery-induced endometriosis showed the enlargement of pelvic lymph nodes.	76
Figure 30 Enlarged pelvic lymph nodes were decreased by the blockage of VEGF-C/VEGFR signaling.	77
Figure 31 Immune cells infiltration was found in mice endometriotic lesions.	78
Figure 32 Blocking VEGF-C signaling reduces immune cells infiltration to endometriotic tissues.	79
Figure 33 The presence of DIE lesions is among the muscle layers of multiple organs in peritoneal cavity.	80
Figure 34 Immune cells are highly infiltrated in DIE tissues.	81
Figure 35 The infiltrated CD11c+IL-17+ immune cells are highly enriched in DIE tissues.	82
Figure 36 The infiltrated IL-17+Th17 immune cells are highly enriched in DIE tissues.	83
Figure 37 IL-17+Th17 cells present in ectopic tissues rather than in normal endometrium.	84
Figure 38 Localization of Th17 cells is near the site of lymphatic tubes.	85
Figure 39 IL-17+Th17 cells present in pelvic lymph nodes from DIE patients..	86
Figure 40 Increased level of IL-17 receptor C (IL17RC), rather than IL17RA, was found in the endometriotic tissues.	87
Figure 41 The gene expression profile of GSE141549 shown by heatmap.	88
Figure 42 NGF expresses significantly higher in endometriotic tissues than normal endometrium.	89
Figure 43 Activated IL-17 signaling promotes neuron innervation in DIE.	90
Figure 44 MMP2, but not MMP9, showed significant higher expression in DIE when compared to control endometrium.	91
Figure 45 The endometrial stromal cells that were pretreated with IL-17 (10 ng/mL) showed higher migratory abilities..	92
Figure 46 Patients with endometriosis showed Increased lymphangiogenesis and immune cell infiltration.	93
Figure 47 Most patients without endometriosis don’t show much lymphangiogenesis and immune cells infiltration in endometrial tissues.	94
Figure 48 Schematic drawing of the procedure analyzing EV-transmitted VEGF-C from patients’ sera.	95
Figure 49 EV could be isolated from patients’ sera by size exclusion chromatography (SEC).	96
Figure 50 More EV release is found in patients with higher severity.	97
Figure 51 Serum from patients with endometriosis showed higher EV-associated VEGF-C.	98
Figure 52 EV released from patients with endometriosis carry higher VEGF-C proteins.	99
Figure 53 EV-associated VEGF-C is higher in the sera of patients with endometriosis..	100
Figure 54 EV-associated VEGF-C in serum is a potential diagnostic marker for endometriosis.	101
Figure 55 Schematic drawing of working model of my dissertation.	102

                                    

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