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系統識別號 U0026-2301201502315700
論文名稱(中文) 基質軟硬度在調控初級近端小管細胞生長與分化中所扮演的角色:慢性腎間質纖維化疾病的應用性
論文名稱(英文) Role of matrix stiffness in the regulation of primary proximal tubular cell proliferation and differentiation:implication in chronic tubulointerstitial fibrosis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 1
出版年 104
研究生(中文) 陳宛君
研究生(英文) Wan-Chun Chen
學號 S58981248
學位類別 博士
語文別 英文
論文頁數 160頁
口試委員 指導教授-湯銘哲
召集委員-楊倍昌
口試委員-謝清河
口試委員-吳佳慶
口試委員-陳鴻震
口試委員-吳明儒
中文關鍵字 基質軟硬度  近端管狀上皮細胞  增生  分化  乙型轉化生長因子誘導之上皮-間質細胞轉化  胞外基質  Klf5  Klf4  YAP1  纖維化 
英文關鍵字 matrix stiffness  proximal tubular epithelial cell  proliferation  differentiation  transforming growth factor-b1-induced epithelial-mesenchymal transition  extracellular matrix  Klf5  Klf4  YAP1  fibrosis 
學科別分類
中文摘要 正常來說,已分化的腎臟近端小管上皮細胞生長於富含laminin的軟性基底膜上。慢性腎間質纖維化疾病其特徵為在組織間隙中有大量胞外基質堆積伴隨著器官硬化進而演變成末期腎臟病。先前研究指出乙型轉化生長因子beta1對於纖維化過程中扮演誘導或促進的重要角色。然而近年來越來越多的研究指出細胞外基質軟硬度亦會調控細胞行為,例如:發育、生長、分化、凋亡及癌化過程。因此我們好奇基質軟硬度對於腎臟的生理及病理發展過程中所扮演的角色。在第一部分研究裡,我們著重於探討胞外基質所提供的化學與物理性刺激相互對細胞行為的調控。當細胞培養於硬性基質上,初級老鼠近端小管上皮細胞將逐漸失去其原有的管狀型態與分化能力,同時伴隨著細胞攤開與增生現象。在此培養環境下,細胞可接受乙型轉型生長因子-beta1的刺激而走向上皮-間質細胞的轉化。若當細胞重於軟性環境下則會反向調控所有現象。另一方面,我們也發現若在軟性基質中增加第一型膠原蛋白的含量一樣可促使細胞攤開、去分化 、增生 及促進乙型轉型生長因子beta1誘導上皮-間質細胞轉化的能力。我們近一步發現硬性基質促進ERK的活化貢獻於其所調控的所有細胞行為。
在第二部分的研究,我們嘗試去探討基質軟硬度如何調控細胞增生及其如何影響慢性腎間質纖維化過程的分子機制。透過微陣列柱及實驗結果,我們推測Krüppel-like factors 5 (Klf5) 及 Krüppel-like factors (Klf4)為可能的參與者。硬性基質會透過ERK的活化誘導Klf5的上升與Klf4的下降。抑制Klf5或強迫Klf4的表現將減少硬性基質所誘導之細胞增生,代表著Klf5及Klf4分別扮演著正向與反向調控細胞增生的角色。
此外,我們亦發現一個對機械力敏感的蛋白,YAP1,可能藉由抑制Klf5蛋白降解進而誘導Klf5蛋白於硬性基質中上升的現象。最後,我們利用單側輸尿管結紮來誘導腎纖維化的動物模式來近一步探討。值得注意的是,若藉由抑制膠原蛋白交連作用而減緩器官硬化可有效的抑制腎小管擴張與不正常增生伴隨著抑制ERK/YAP1/Klf5/Cyclin D1的上升及保有Klf4的表現。
總結來說,我們提出機械力刺激如何透過對其敏感的轉錄因子參與腎臟的生理及病理發展的調控。此研究將對慢性腎間質纖維化疾病的進程提供全新的力學角度。
英文摘要 Normally, differentiated renal proximal tubular epithelial cells (PTECs) reside on soft basement membrane containing laminin-rich extracellular matrix (ECM). Chronic tubulointerstitial fibrosis is characterized by the accumulation of collagen with tissue stiffening and finally leads to the end-stage renal disease. Previous studies showed that transforming growth factor-beta 1 (TGF-beta1) played the potent initiator and/or enhancer for fibrogenesis. However, accumulated studies also indicate that the matrix stiffness also regulate cell behaviors, i.e. development, proliferation, differentiation, apoptosis and tumorigenesis. We were curious about the role of matrix stiffness in the physiological and pathological development in the kidney. In the first part of study, we focused on the interplay between chemical cues and physical cues from ECM on the regulation of cell behaviors. Primary culture of mice PTECs (mPTECs) gradually lost their tubular morphology and differentiated properties with the increase of cell spreading and proliferation when cultured on stiff matrix. Furthermore, the cells responded to TGF-beta1 and underwent epithelial-mesenchymal transition (EMT) under stiff matrix. However, these phenomena were reversed when cells were cultured on soft matrix. On the other hand, an increase of collagen amount in soft matrix also facilitated cell spreading, de-differentiation, proliferation, and TGF-beta1-induced EMT, indicating that both soft matrix and basement membrane signals were required for the maintenance of the physiological function of mPTECs. Furthermore, we identified that ERK activation controlled by stiff matrix contributed to all the cellular behaviors regulated by stiff matrix.
In the second part of study, we attempted to verify the novel mechanism of how matrix stiffness controls cell proliferation and its significance on the pathogenesis of chronic tubulointerstitial fibrosis. Based on the results obtained from oligo-microarray and experiments, we purposed Krüppel-like factors 5 (Klf5) and Krüppel-like factors (Klf4) as the possible candidates. Stiff matrix upregulated Klf5 and downregulated Klf4 in mRNA and protein levels via ERK signal. Suppression of Klf5 or forced expression of Klf4 stunted stiff matrix-induced cell proliferation as confirmed by nuclear Cyclin D1 and EdU intensity, indicating that Klf5/Klf4 served as the positive/negative regulators of cell proliferation, respectively. Furthermore, we suggested that mechanosensitive Yes-associated protein 1 (YAP1) may contribute to stiff matrix induced Klf5 upregulation through preventing Klf5 degradation. Finally, we applied the in vivo model of unilateral ureteral obstruction to induce fibrosis. Notably, alleviation of tissue stiffening by blocking collagen crosslinker efficiently suppressed tubular dilatation and abnormal proliferation with the upregulation of ERK/YAP1/Klf5/Cyclin D1 axis and the downregulation of Klf4.
In conclusion, we demonstrate that how mechanical cues are involved in the regulation of renal physiological functions and pathological progression via mechanosensitive transcription factors. This study provides us a new insight into the pathogenesis of chronic tubulointerstitial fibrosis from the physical view.
論文目次 Contents
Abstract............1
Abstract in Chinese..........3
Acknowledgement..........4
Contents............7
Table contents............11
Figure contents..........12
Abbreviations............15
Chapter 1 Introduction.........18
1-1 Kidney...........18
1-1.1 Physiological function of the kidneys.......18
1-1.2 Pathological progression of kidneys: Tubulointerstitial fibrosis...18
1-1.3 Physiological functions of proximal tubules (PTs)....20
1-2 Essential environmental cues in the kidney.......23
1-2.1 The chemical basis of the kidneys........23
1-2.1.1 ECM components.........24
1-2.1.2 Growth factors...........26
1-2.2 The physical basis of the kidneys.......26
1-2.2.1 Fluid shear stress.........27
1-2.2.2 Stretch..........28
1-2.2.3 Matrix stiffness..........29
1-3 Matrix stiffness..........30
1-3.1 The regulatory mechanism in the control of matrix stiffness...30
1-3.1.1 ECM synthesis and degradation.......30
1-3.1.2 ECM crosslinks..........31
1-3.1.2.1 Enzymatic crosslinker.........31
1-3.1.2.2 Non enzymatic ECM crosslinkers........33
1-3.2 The importance of maintaining tissue mechanics.....33
1-3.2.1 Cancer...........33
1-3.2.2 Sclerosis...........34
1-3.2.3 Tissue fibrosis.........34
1-3.3 The role of matrix stiffness on cell behaviors.....35
1-3.3.1 Spreading..........35
1-3.3.2 Proliferation.........36
1-3.3.3 Differentiation..........36
1-3.3.4 Stem cell differentiation.........37
1-3.3.5 Apoptosis..........37
1-3.3.6 Migration...........38
1-3.3.7 Invasion..........38
1-4 Mechanosensing and mechanotransduction machinery of matrix stiffness.38
1-4.1 Mechanosensing machinery.........38
1-4.2 Mechanotransduction machinery.......40
1-4.2.1 Mitogen activated protein kinases (MAPK).....40
1-4.2.2 Yes-associated protein 1 (YAP1)........41
1-5 TFs involved in cell proliferation and differentiation....42
1-5.1 Runt-related transcription factor (Runx) family......43
1-5.2 CCAAT enhancer-binding proteins (C/EBPs) family....43
1-5.3 Activating transcription factor (Atfs) family......44
1-5.4 Zonula occludens 1-associated nucleic acid binding protein (ZONAB)...44
1-5.5 Hepatocyte Nuclear Factor (HNF) family.......45
1-5.6 Krüppel-like factors (Klfs) family........46
Chapter 2 Materials and Methods........48
2-1 Cell lines and cell culture.........48
2-2 Isolation of primary mPTECs from mice kidneys.....48
2-3 Matrix preparation.........49
2-4 Collection of cell lysates and Western blotting......50
2-5 RNA extraction and reverse transcription PCR (RT-PCR).....51
2-6 Immunofluorescence staining.......52
2-7 Evaluation of cell proliferation with Click-iT®EdU kits.....53
2-8 Microarray database and ingenuity pathway analysis....53
2-9 Assessment of tissue/cell mechanical properties by atomic force microscopy..55
2-10 Establish mCherry-Klf4 expression clones, and plasmid construction...55
2-11 Establish lentivirus-delivery shRNA of Klf5......56
2-12 Nuclear and cytoplasmic fractionation........56
2-13 Unilateral ureteral obstruction (UUO) in mice..........56
2-13 Immunohistochemistry (IHC).......57
2-14 Statistics..........57
Chapter 3 Regulation of proximal tubular cell differentiation and proliferation in primary culture by matrix stiffness and ECM components.....58
Abstract............59
Abstract in Chinese...........60
Introduction............61
Results............64
Discussion...........71

Chapter 4 Inverse expression of Klf4 and Klf5 mediated stiff substrate-induced proliferation in primary mice proximal tubular cells: the implications in chronic tubulointerstitial fibrosis.........77
Abstract............78
Abstract in Chinese...........79
Introduction............80
Results............83
Discussion...........90
Chapter 5 Summary and prospect........94
References...........98
Figures............120
Curriculum Vitae...........159
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