包覆性腹膜硬化症相關miRNAs透過間質幹細胞衍生外泌體對腹膜纖維化過程的影響之研究

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葉子維(Tzu-Wei Yeh) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

包覆性腹膜硬化症相關miRNAs透過間質幹細胞衍生外泌體對腹膜纖維化過程的影響之研究
(The study of effects of WJMSC-derived exosomes with encapsulated peritoneal sclerosis related miRNAs on peritoneal fibrosis process)

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至系統瀏覽論文 (2028-9-12以後開放)

摘要(中)

腹膜透析 (Peritoneal dialysis, PD) 是一種廣為人知的末期腎病的腎臟替代療法 (Renal replacement therapy)。長期使用高濃度葡萄糖透析液的洗腎病患有較高機率會誘發間皮到間質 (MMT) 的轉換，進而引發腹膜纖維化 (Peritoneal fibrosis)。包覆性腹膜硬化症(Encapsulating peritoneal sclerosis, EPS) 是長期使用腹膜透析而產生的致死併發症，造成腹膜增厚且纖維化並產生纖維繭將直腸包覆，最後造成腸道的阻塞。至今皮質類固醇 (Corticosteroid)、泰莫西芬 (Tamoxifen)、抗免疫藥物已被證實能夠有效的改善包覆性腹膜硬化症的情況，但是此疾病的致死率仍然居高不下。相對於不同器官所分離出來的間質幹細胞，華通氏膠質 (Wharton′s jelly, 一種臍帶內的膠狀組織) 的間質幹細胞分泌出來的外泌體的產量較高，因此利用WJMSC (華通氏膠質膠質幹細胞) 作為外泌體的來源。外泌體內含小分子核糖核酸、訊號核糖核酸及蛋白質…等訊號傳遞分子，進入目標細胞並調控功能。在先前實驗室研究結果顯示，在包覆性腹膜硬化症患者的透析液中，miR-17-5p、miR-155-5p、miR-202-3p、miR-422a和miR-483-5p的表現量皆有顯著下調的情況，經過後分析後五個miRNAs具備作為生物標記及調控腹膜硬化症的潛力miRNAs。在本實驗中，首先用WJMSC的條件培養基加入RNase A 以及RNase A/Triton X-100，以初步挑選5個候選miRNAs何者包裹在外泌體裡而不是存在於外泌體膜狀結構之外。證明完miRNA存在於外泌體與否，下一步利用生物支架 (3D-Scaffold) 培養WJMSC並萃取外泌體，並發現相較於培養盤，生物支架能夠提供更好的外泌體產率。接著了解五個候選miRNAs 在WJMSC衍生外泌體的表現量，從結果上發現miR-17-5p表現量相對於其他四個候選miRNA高出許多，使我們開始探討WJMSC衍生外泌體所富含的miR-17-5p是否能夠影響由TGF-β1所誘導MMT。首先將WJMSC所分泌外泌體加入由TGF-β1所誘導人類肋膜間皮細胞 (MeT-5A)，觀察到20 µg/ml的外泌體可以透過降低間質性蛋白表現 (MMP-2和Vimentin)，能夠減少由TGF-β1所誘導MMT而產生的細胞形變。下一步，為了能夠證實外泌體中的miR-17-5p是調控MMT的媒介之一，將miR-17-5p過表現在外泌體中並加入由TGF-β1所誘導的MeT-5A，研究結果顯示，間質性蛋白表現 (MMP-2和Vimentin) 及細胞形變會有下降的趨勢。綜合上述結論，外泌體內的miR-17-5p可以在TGF-β1所誘導MeT-5A所產生的MMT扮演著抑制調控的角色。接著在先前研究中，miR-17-5p 和miR-483-5p皆是作為減緩MMT進程的潛力miRNAs且能夠調控不同的MMT相關蛋白。因此我們想了解過表現miR-17-5p外泌體、過表現miR-483-5p外泌體以及結合miR-17-5p和miR-483-5p過表現外泌體的組別 (Combination) 是能夠有效的抑制由TGF-β1所誘導的MMT。在研究中發現，miR-17-5p過表現外泌體、miR-483-5p過表現外泌體及結合miR-17-5p和miR-483-5p過表現外泌體的組別都能有效得降低由TGF-β1所誘導的細胞形變。MMT相關的蛋白調控方面，miR-17-5p過表現外泌體能夠調控間質性蛋白 (MMP-2)，miR-483-5p過表現外泌體在間質性蛋白 (TypeΙcollagen、MMP-2和α-SMA) 都有調控其表現量的效果，而且相較於單一miRNA 過表現外泌體，結合miR-17-5p和miR-483-5p過表現外泌體的組別在TypeΙcollagen以及MMP-2的抑制能力有增強的趨勢，間接證明在這兩種miRNAs過表現外泌體共同作用下，其效力對於上述TypeΙcollagen和MMP-2蛋白具有加乘的效果。在細胞收縮能力方面，miR-17-5p 過表現外泌體能減弱TGF-β1所誘導的間皮細胞凝膠收縮的能力，而miR-483-5p過表現外泌體及結合miR-17-5p和miR-483-5p過表現外泌體的組別則否。綜合上述結果，對於MMT的調控，結合miR-17-5p 和miR-483-5p過表現外泌體也是具有潛力的方式。未來對於miR-17-5p 和miR-483-5p過表現外體調控MMT的機制也能更深入研究及探討。

摘要(英)

Peritoneal dialysis (PD) was a renal replacement therapy against end-stage renal diseases. Long-term use of high-glucose dialysate could induce mesothelial-to-mesenchymal transition (MMT) in peritoneal mesothelial cells, resulting in peritoneal fibrosis (PF). Encapsulating peritoneal sclerosis (EPS) is a rare complication of end-stage renal disease for long-term of PD treatment. EPS formation has been confirmed to make peritoneum thicker and fibrotic, which causes the formation of fibrous cocoon wrapping bowel leading intestinal obstruction. EPS have been reported to be improved with corticosteroids, tamoxifen, or immunosuppressive agents, but the mortality rate for EPS was still high (25%–55%). Compare with other types of mesenchymal stem cells, WJMSCs (Wharton’s jelly mesenchymal stem cells) had the high yield of exosomes in previous report. Exosomes have been reported to deliver important information such as miRNAs, mRNAs, and proteins into the target cells and to mediate the biological behaviors. Our previous study showed that the expressions of miR-17-5p, miR-155-5p, miR-202-3p, miR-422a, and miR-483-5p could identify EPS in peritoneal effluent. In our study, the conditioned medium of WJMSC cells was treated with Triton X-100, RNase A alone or combination in order to test these miRNAs are released as the free form or encapsulated into exosomes. The results showed that miR-17-5p was wrapped with membrane such as exosomes instead of being released directly and miR-17-5p expression was abundant in WJMSC-derived exosome. Next, WJMSC-derived exosomes was isolated with 3D-scaffolds, and we found that the yield of exosomes with a 3D-scaffold was larger than 2D-culture. In our result, Mesothelial-to-mesenchymal transition (MMT) induced by TGF-β1 in human mesothelial cells (MeT-5A) could be inhibited after 20 µg/ml WJMSC-derived exosome treatment, which was investigated by down-regulation of mesenchymal marker (MMP-2 and Vimentin) and inhibition of cellular morphological changes by measurement of five cellular metrics (Size, Area, Length, Perimeter, Circularity). MMP-2, Vimentin expressions and cellular morphological changes were decreased after treatment of miR-17-5p-overexpressed exosomes. As stated above, exosomal miR-17-5p from WJMSC was a one of mediators to decrease MMT induced by TGF-β1 in MeT-5A. In our previous study, we found that miR-17-5p and miR-483-5p were potential miRNA candidates for EPS. Therefore, we investigated that whether miR-17-5p-overexpressed exosomes and miR-483-5p-overexpressed exosomes and combination of miR-483-5p-overexpressed exosomes and miR-17-5p-overexpressed exosomes could reduce the MMT progression induced by TGF-β1 in MeT-5A. In our result, miR-17-5p-overexpressed exosomes and miR-483-5p-overexpressed exosomes and combination of two different overexpressed exosomes could reduce cellular morphological changes induced by TGF-β1. Additionally, miR-17-5p-overexpressed exosomes could down-regulate the mesenchymal marker (MMP-2) and miR-483-5p- overexpressed exosomes could down-regulate the mesenchymal marker (TypeΙcollagen, MMP-2 and α-SMA). Most importantly, compare with single miRNA-overexpressed exosomes, combination of two different overexpressed exosomes could inhibit the expressions of mesenchymal marker (TypeΙcollagen, MMP-2) more effectively. In regard to contractile activity of collagen gel in human mesothelial cell (MeT-5A), miR-17-5p-overexpressed exosomes could attenuate the TGF-β1 induced contractile activity by measurement of collagen gel contraction assay, but miR-483-5p-overexpressed exosomes and combination did not. As stated above, the combination of miR-483-5p-overexpressed exosomes and miR-17-5p-overexpressed exosomes also could be a potential role for reducing MMT progression. In the future, we will continue to explore the mechanism of miR-17-5p and miR-483-5p-overexpressed exosomes in MMT induced by TGF-β1.

關鍵字(中)

★ 外泌體

關鍵字(英)

★ Exosome

論文目次

目錄
中文摘要 i
Abstract iii
致謝 vii
圖目錄 xi
表目錄 xii
Abbreviation list xiii
一、介紹 (Introduction) 1
1. 外泌體 (Exosome) 1
1-1 間質幹細胞衍生外泌體 (MSC-derived exosome) 1
1-2 間質幹細胞衍生外泌體的治療應用 (Therapeutic application of MSC-derived 3
exosome) 3
2. 包覆性腹膜硬化症 ( Encapsulated peritoneal sclerosis) 5
2-1 腹膜纖維化的形成 (Formation of peritoneal fibrosis) 5
2-2 包覆性腹膜硬化症的發生 (Development of encapsulated peritoneal sclerosis) 7
2-3 包覆性腹膜硬化症的診斷與治療 (Therapy of encapsulated peritoneal sclerosis) 7
3. 由轉化生長因子誘導的間質變間皮轉換 (MMT induced by TGF-β1) 8
4. 小分子核醣核酸 (MicroRNA) 10
4-1 小分子核醣核酸的生成 (Genesis of microRNA) 10
4-2 小分子核醣核酸的調控及應用 (Application and regulation of microRNA) 10
5. 研究目的 (Purpose of the study) 12
二、實驗材料及方法 (Materials and methods) 13
1. 實驗材料 (Materials) 13
1-1 細胞株 (Cell lines) 13
1-2 小分子核糖核酸模擬物 (MiRNA mimics) 13
1-3 抗體 (Antibodies) 13
1-4 螢光染劑 (Fluorescent reagent) 13
1-5 外泌體轉染套組 (Exosome transfection kit) 14
2. 實驗方法 (Methods) 14
2-1 藉由Triton X-100和RNase A預測外泌體內EPS相關miRNA的包覆情形 (The prediction of EPS-related miRNAs in exosomes with Triton X-100 & RNase A) 14
2-2細胞及外泌體蛋白質樣本製備 (Preparation of cell and exosome protein sample) 14
2-3 西方墨點法 (Western Blot) 15
2-4 螢光染色 (Fluorescent staining) 15
2-5 外泌體純化 (Exosome isolation) 16
2-6 轉染外泌體 (Exosome transfection) 16
2-7 收集生物支架所培養的外泌體 (Collect exosomes attached in a 3D-scaffold) 16
2-8 即時定量聚合酶連鎖反應 (RT-qPCR) 17
2-9 膠原凝膠收縮測定 (Collagen gel contraction assay) 17
2-10 統計 (Statistics) 17
三、實驗結果 (Results) 18
1. 利用Triton X-100和RNase A 預測EPS相關miRNAs在外泌體的包覆情形 18
2. 利用生物支架 (3D-scaffold) 培養WJMSC並增加外泌體產率 19
3. EPS相關miRNAs在WJMSC衍生外泌體的表現量 19
4. WJMSC衍生外泌體內的miR-17-5p調控TGF-β1誘導的細胞形變 20
5. WJMSC衍生外泌體內的miR-17-5p調控MMT相關蛋白 21
6. MiR-17-5p和miR-483-5p透過外泌體調控細胞形變及MMT相關蛋白 22
7. MiR-17-5p和miR-483-5p透過外泌體調控細胞凝膠收縮能力 23
四、結論與討論 (Conclusions and discussions) 25
1. 探討利用Triton X-100和RNase A預測EPS相關miRNAs在外泌體的包覆情形 25
2. 探討WJMSC衍生外泌體中的miR-17-5p對細胞形變的影響 25
3. 探討WJMSC衍生外泌體中的miR-17-5p對MMT相關蛋白的影響 25
4. 探討利用EPS相關miRNAs透過WJMSC衍生外泌體對大鼠中腹膜纖維化的影響 26
5. 探討MiR-17-5p和miR-483-5p透過外泌體調控MMT相關蛋白及凝膠收縮能力 26
6. 探討其他EPS相關miRNAs透過外泌體對於MMT的影響 27
7. 探討EPS相關miRNAs透過外泌體進入目標細胞的情形 27
8. 探討利用生物反應器 (Bioreactor system) 大量收集WJMSC衍生出的外泌體 28
9. 未來展望 28
五、參考資料及文獻 (Reference) 30

參考文獻

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指導教授

馬念涵(Nianhan Ma)

審核日期

2023-8-16

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