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系統識別號 U0026-2907202018121300
論文名稱(中文) 由免疫調節及血管新生所誘導之周邊神經修復
論文名稱(英文) Immunomodulation- and angiogenesis-led peripheral nerve regeneration
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 108
學期 2
出版年 109
研究生(中文) 黃子婕
研究生(英文) Tzu-Chieh Huang
學號 S58041187
學位類別 博士
語文別 英文
論文頁數 87頁
口試委員 指導教授-吳佳慶
召集委員-楊尚訓
口試委員-劉校生
口試委員-吳尚蓉
口試委員-林劭品
中文關鍵字 周邊神經修復  凝血調節蛋白  巨噬細胞極化  內皮導向細胞  胞外體 
英文關鍵字 Peripheral nerve regeneration  Thrombomodulin  macrophage polarization  Endothelial lineage cell  Exosome 
學科別分類
中文摘要 受傷組織當中過度的發炎反應往往會導致組織再生過程緩慢且再生結果不佳。對於再生效率往往不佳的周邊神經系統,調控發炎反應以促進神經再生此治療策略越發受到重視,然而,目前缺乏實用之治療策略可以達到上述的結果。凝血調節蛋白 (Thrombomodulin, TM) 是具有五個功能結構域的穿膜醣蛋白。在所有的結構域中,其中類凝集素結構域 (Lectin-like domain) 具有抑制發炎的作用。在本實驗中,我們利用單核球細胞株發現TM具有調節發炎典型活化巨噬細胞 (M1) 成為再生非典型巨噬細胞 (M2) 之功能,我們亦以截斷神經動物模式驗證由凝血調節蛋白所促進的再生非典型巨噬細胞極化對於受傷神經之療效。我們的研究顯示外加的凝血調節蛋白可以促進神經之再生,及其肌肉功能性之恢復。此外,凝血調節蛋白亦可透過增加再生非典型巨噬細胞數量達到促進神經軸突 (axon) 延長及再隨鞘化。除了免疫調節,我們亦發現促進血管新生及營造一促血管再生的微環境對於神經再生相當重要。本研究探討內皮導向細胞 (endothelial lineage cell, ELC) 之胞外體 (exosome) 對於促進神經再生之潛力,我們發現相較於脂肪幹細胞 (Adipose-derived stem cell, ASC),內皮導向細胞表現大量的血管新生微小核醣核酸 (microRNA) 126,相同地,內皮導向細胞之胞外體亦含有大量的微小核醣核酸-126。我們亦發現內皮導向細胞的條件化培養液 (conditioned medium) 可以促進背根神經節外植體之神經突觸生長的數量,同時,內皮導向細胞的胞外體也可促進許旺氏細胞 (Schwann cell) 之成熟。綜合上述所言,本研究證實了利用免疫調節及促進血管新生以加強周邊神經再生的新穎治療策略。
英文摘要 Excessive inflammation within damaged tissue usually leads to delayed and insufficient regeneration. In peripheral nervous system, where fully recovery doesn’t occur frequently, modulating the inflammatory response to promote nerve regeneration has become more and more promising, however, there is a lack of practical therapeutic strategy for doing so. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. Amount all the domains, lectin-like domain of TM shows ability in suppressing inflammatory response. In the current study, we revealed the potential of TM in switching pro-inflammatory type1 macrophages (M1) to anti-inflammatory type2 macrophage (M2) by using THP1 cell. We also evaluated the therapeutic effect of TM-enhanced M2 transition on transected sciatic nerve. Our in vivo finding showed that TM treatment led to a better nerve regeneration and further preserved the effector muscle function. Furthermore, the supplementation of TM also exhibits a remark function in promoting axon elongation and remyelination through increasing the number of M2. Beside immunomodulation, we also found that enhancing angiogenesis and creating a pro-angiogenetic microenvironment is critical for nerve regeneration. In the current study, we also evaluated the potential of endothelial lineage cell (ELC) –derived exosome in enhancing nerve recovery. In comparison to adipose-derived stem cell (ASC), ELC exhibited higher expression of the angiogenetic microRNA (miR)-126. Correspondently, the miR-126 was also enriched in ELC-derived exosomes. We found the ELC conditional medium increased the number of outgrowing neurite in the DRG explants. Concurrently, ELC-exosome exhibited ability in promoting Schwann cell (SC) maturation. Taken together, the current study proved novel therapeutic strategies for peripheral nerve regeneration by immunomodulation and enhancing angiogenesis.
論文目次 中文摘要..................................................Ⅰ
Abstract………………………………………………………………Ⅱ
Table Contents………………………………………………………………Ⅲ
Figure Contents ……………………………………………………Ⅵ
Introduction…………………………………………………………1
1-1 Peripheral nerve injury………………………………………2
1-2 Immunomodulation for peripheral nerve injury…………2
1-3 Macrophage in peripheral nerve injury……………………3
1-4 Thrombomodulin…………………………………………………4
1-5 Endothelial cells and Angiogenesis in peripheral nerve injury………………6
1-6 Endothelial cell transplantation using stem cell-derived EPCs…………………8
1-7 Stem cell-derived exosomes…………………………………9
Chapter 2. Hypothesis……………………………………………11
Chapter 3. Materials and Methods……………………………13
3-1 THP-1 cell maintenance and differentiation…………14
3-2 In vitro macrophage polarization and the application of TM……………………14
3-3 Primary SC isolation and inflammatory responses……15
3-4 Adipose-derived stem cell (ASC) maintenance and differentiation of endothelial lineage cell (ELC)………15
3-5 Preparation of conditioned medium (CM)……………16
3-6 Exosome isolation and purification…………………16
3-7 Creation of an animal model for sciatic nerve regeneration…………17
3-8 Measurement of gene expression and luciferase reporter assay…………………18
3-9 Protein expression analysis………………………………19
3-10 Inhibition of c-Myc, p-STAT6, and PPARγ……………20
3-11 Detection of ROS levels…………………………………21
3-12 Toluidine blue staining and transmission electron microscopy (TEM)………21
3-13 Immunohistochemistry staining…………………………22
3-14 Image quantification and analysis……………………23
3-15 Statistical analysis……………………………………24
Chapter 4. Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching…………25
4-1 TM inhibited M1 inflammatory cytokine production and caused a switch towards the M2 phenotype……………………26
4-2 TM-conditioned media reduced SC inflammation…………28
4-3 The administration of TM promoted peripheral nerve regeneration and restored innervated muscle…………………29
4-4 TM modulated the tissue cytokine profile to create a proregenerative microenvironment………………………30
4-5 TM reduced glial scarring and pan-macrophage number by increasing the M2/M1 cell ratio…………………………………31
4-6 Summary of immunomodulation for PNS regeneration……33
Chapter 5. Angiogenesis-led nerve regeneration……………34
5-1 Endothelial lineage cell (ELC) exhibited high expression levels of therapeutic miRs………………………………………35
5-2 ELC-exosome exhibited distinct features as compared to ASC- exosome…………………………………………………………35
5-3 ELC-exosome promoted the differentiation of Schwann cell (SC) through the downregulation of Sox2 via miR-126………36
5-4 Secretory factor derived from ELC enhanced the neurite outgrowth of DRG explant…………………………………………38
5-5 Future perspectives …………………………………………40
5-6 Summary of angiogenesis-led regeneration for PNS……43
Chapter 6. Discussion and Conclusion…………………………44
Chapter 7. References……………………………………………54
Chapter 8. Figures………………………………………………60
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