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系統識別號 U0026-2102202023001100
論文名稱(中文) 探討發炎巨噬細胞誘發胞外基質重塑對於脂肪細胞功能的影響
論文名稱(英文) Effect of inflamed macrophage-induced extracellular matrix remodeling on adipocyte function
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 108
學期 1
出版年 109
研究生(中文) 高伶甄
研究生(英文) Ling-Zhen Kao
學號 S36064054
學位類別 碩士
語文別 英文
論文頁數 65頁
口試委員 指導教授-蔡曜聲
口試委員-湯銘哲
口試委員-蔡少正
口試委員-邱文泰
中文關鍵字 巨噬細胞  胞外基質重塑  脂肪細胞功能 
英文關鍵字 Macrophage  ECM remodeling  adipocyte functions 
學科別分類
中文摘要  過去40年中,全世界肥胖比例大大的提升,近期的研究顯示,肥胖會伴隨著脂肪組織纖維化。根據報導指出,細胞胞外基質 (ECM) 交聯 (crosslinking) 的增加會導致組織纖維化並且增加組織的硬度,Lysyl oxidase(LOX) 為膠原蛋白交聯的關鍵酵素,會造成胞外基質硬化。LOX 最初是呈現 pro-LOX 的形式,經由蛋白酶切割成有功能的形式 LOX,而這些進行切割的蛋白酶包含 BMP-1, MMP-2, TLL1 及 TLL2。在我們實驗室之前的結果表明,發炎反應會刺激巨噬細胞而增加 LOX 的產生,因此我們假設發炎的巨噬細胞在胞外基質重塑及脂肪細胞失能中扮演關鍵角色。我們首先發現 LOX 存在於肥胖小鼠 (ob/ob) 脂肪組織中的巨噬細胞聚集處,並且在肥胖小鼠的腹腔巨噬細胞中發現增加了 LOX 的產生及分泌。在體外實驗中,利用巨噬細胞株 Raw 264.7 並給予細胞激素誘導發炎反應時,發現 pro-LOX, LOX, BMP-1 及 MMP-2 的生產及分泌增加。接著我們應用了體外膠原蛋白凝膠系統來測試發炎的巨噬細胞是否重塑了胞外基質的微環境,首先將 Raw 264.7 細胞培養在被 FITC 標定的膠原蛋白凝膠上,然後利用細胞激素作為發炎症狀的刺激物,再將在凝膠上的細胞進行去細胞過程,在免疫螢光顯微鏡的觀察中發現,細胞激素處理後增加了殘留巨噬細胞附近膠原纖維的厚度。我們在這種巨噬細胞處理過的凝膠上進一步培養成纖維細胞 (fibroblasts),以測試其物理性質,我們發現經由細胞激素處理的巨噬細胞加工凝膠,增加了膠原蛋白凝膠的收縮能力以及膠原纖維的排列與厚度。因此,發炎的巨噬細胞能夠通過基質收縮並增加膠原纖維排列與厚度來重塑胞外基質。有趣的是,在巨噬細胞處理後的膠原蛋白凝膠上培養分化的 3T3-L1 脂肪細胞顯示出減少脂肪細胞功能相關基因的表現量,我們的研究提供了脂肪細胞與胞外基質之間的關聯,特別是經由發炎巨噬細胞的重塑。
英文摘要 Over the last 40 years, obesity rates around the world have significantly increased. Recent studies suggest that obesity is accompanied by adipose tissue fibrosis. An increase of extracellular matrix (ECM) crosslinking has been shown to cause tissue fibrosis, followed by increasing tissue stiffness. Lysyl oxidase (LOX) is an enzyme crucial for collagen crosslinking that causes ECM stiffening. LOX is synthesized as a pro-LOX originally and processed by proteases, such as BMP1, MMP2, TLL1, and TLL2. Our previous results suggest that LOX is increased by macrophages upon the inflammatory stimulation. We therefore hypothesize that inflamed macrophages play a pivotal role in the ECM remodeling and adipocyte dysfunction. We first found that LOX is present in the macrophage-enriched region in the adipose tissue of obese ob/ob mice. Peritoneal macrophages from ob/ob mice showed increased LOX production and secretion. In vitro cytokine treatment on Raw 264.7 cells induced the production and secretion of pro-LOX, LOX, BMP-1 and MMP-2. We then applied an in vitro collagen gel system to test whether inflamed macrophages reset the ECM microenvironment. Raw 264.7 cells were firstly cultivated on the FITC-conjugated collagen gel, and then treated cytokines as an inflammatory stimulation, followed by a decellularization procedure. Immunofluorescence microscopy revealed that cytokine treatment increased collagen fiber thickness near residual macrophages. We further cultured fibroblasts on this macrophage-processed gel to test their physical property. We found that cytokine treatment increased collagen gel contraction and the alignment and thickness of collagen fiber in macrophage-processed gel. Thus, inflamed macrophages are able to remodel the ECM via matrix contraction and increasing collagen fiber alignment and thickness. Interestingly, differentiated 3T3-L1 cells, cultivated on the macrophage-processed collagen gel, showed downregulation in adipocyte functional marker genes. Our study provides a novel crosstalk between adipocyte and ECM, particularly remodeled by inflamed macrophages.
論文目次 Contents
Abstract ·················································································i
Abstract in Chinese ·································································iii
Acknowledgments···································································iv
Contents················································································v
Introduction ···········································································1
Obesity·····························································································1
Adipocyte ·························································································1
Adipocyte dysfunction ··········································································2
Adipose tissue inflammation ···································································2
Adipose tissue macrophage (ATM) ···························································2
Adipose tissue extracellular matrix (ECM) ··················································3
ECM remodeling·················································································3
Adipose tissue ECM remodeling ······························································4
Tissue fibrosis and stiffness ····································································4
Adipose tissue fibrosis and stiffness ··························································5
Lysyl oxidase (LOX) ············································································5
Focal adhesion (FA) ·············································································6
Significance·······················································································7
Material and Method································································8
Cell line and culture ·············································································8
Differentiation of 3T3-L1·······································································8
Peritoneal macrophage isolation ·······························································8
Protein extraction ················································································9
Western blot·······················································································9vi
RNA extraction··················································································10
Reverse transcription PCR·····································································10
Real-time PCR···················································································10
Cell transfection ·················································································11
Immunofluorescence (IF) ······································································11
Opal Multiplexed IHC··········································································12
Collagen gel preparation and decellularization ·············································12
Conditioned medium-processed collagen gel preparation ································13
Macrophage-processed collagen gel preparation···········································13
Atomic force microscopy (AFM)·····························································13
Gel contraction assay ···········································································14
Data analysis·····················································································14
Results ·················································································15
LOX is upregulated and associated with macrophage in obese adipose tissue ········15
LOX processing proteins are upregulated and associated with macrophage in obese
adipose tissue ····················································································15
LOX and ECM cross-linking factors are upregulated in peritoneal macrophages of
obese mice ·······················································································16
The inflammatory stimulation upregulated ECM cross-linking factors in macrophages
·····································································································16
Downregulation of adipocyte functional markers by culturing them on the collagen
gel that was processed by the conditioned medium from inflamed macrophages ·····17
Downregulation of adipocyte functional markers by culturing them on the collagen
gel that was processed by inflamed macrophages··········································18
Inhibition of LOX processing proteins did not affect collagen gel rigidity ············18vii
Macrophages alone had no effect on contraction of the collagen gel ···················19
Increased collagen fiber intensity in inflamed macrophage-processed collagen gel ··19
Increased contraction of inflamed macrophage-processed gel ···························20
Increased collagen fiber thickness and alignment with fibroblasts on inflamed
macrophage-processed gel·····································································20
Increased collagen fiber thickness by differentiated adipocytes on inflamed
macrophage-processed gel·····································································21
Increased YAP nuclear translocation in differentiated adipocytes on inflamed
macrophage-processed gel·····································································21
Increase of FAK activation in differentiated adipocytes on macrophage-processed
collagen gel ······················································································22
Discussion·············································································23
Induction of macrophage LOX by various inflammatory stimuli························23
Modification of collagen gel by direct culturing or conditioned medium of
macrophages ·····················································································24
Production of LOX by macrophages ·························································25
Maturation of LOX by macrophages·························································26
Expression of LOX and its processing proteins in obesity································27
Downregulation of adipocyte functional markers by culturing adipocytes on the
collagen gel processed by inflamed macrophages or the conditioned medium from
inflamed macrophages.·········································································28
Macrophage myofibroblast transition························································28
The contraction ability of macrophages and fibroblasts···································29
ECM remodeling in macrophage-processed collagen gel·································29
The interaction between ECM and cell ······················································30viii
The mechanotransduction to link YAP nuclear translocation·····························31
Conclusion ············································································32
Reference ·············································································33
Tables··················································································38
Figures·················································································40
Figure 1. LOX and macrophage expression in wild type (WT) and obese (ob/ob) mice
adipose tissue ····················································································40
Figure 2. LOX processing proteins and macrophage expression in wild type (WT) and
obese (ob/ob) mice adipose tissue ····························································42
Figure 3. Obesity-stimulated LOX expression in peritoneal macrophages derived from
wild type (WT) and obese (ob/ob) mice ·····················································43
Figure 4. Cytokine-stimulated LOX family and LOX processing proteins expression
in macrophages ··················································································44
Figure 5. Substrate stiffness and adipocyte functional markers of differentiated
adipocyte cultivated on the collagen gel processed by conditioned medium from
macrophages ·····················································································45
Figure 6. Substrate stiffness and adipocyte functional markers of differentiated
adipocyte cultivated on the collagen gel processed by conditioned medium from
transfecting siLOX macrophages ·····························································46
Figure 7. Substrate stiffness and adipocyte functional markers of differentiated
adipocyte cultivated on macrophage-processed collagen gel·····························47
Figure 8. Effect of LOX expression and substrate stiffness in LOX processing protein
inhibitors treatment ·············································································49
Figure 9. Gel contraction assay of macrophages on collagen gel ························50
Figure 10. Collagen fiber thickness of macrophage-processed collagen gel ···········53ix
Figure 11. Gel contraction assay of by 3T3-L1 fibroblasts on macrophage-processed
collagen gel ······················································································55
Figure 12. Collagen fiber thickness and alignment with fibroblasts on macrophageprocessed collagen gel··········································································59
Figure 13. Collagen fiber thickness with differentiated adipocyte on macrophageprocessed collagen gel··········································································60
Figure 14. The location of YAP in differentiated adipocyte on macrophage-processed
collagen gel ······················································································61
Figure 15. Focal adhesion and their downstream proteins in differentiated adipocyte
on macrophage-processed collagen gel ······················································62
Figure 16. The residual effect of LPS on different matrix ································64
Figure 17. -SMA expression in adipose tissue (in vivo) and in macrophages (in
vitro) ······························································································65
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