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研究生:黃柏雅
研究生(外文):Po-Ya Huang
論文名稱:低能量光照刺激促進大鼠骨髓間葉幹細胞之遷移能力
論文名稱(外文):Low Level Light Therapy Enhances the Migration of Mesenchymal Stem Cells Derived from Rat Bone Marrow
指導教授:李文婷李文婷引用關係
指導教授(外文):Wen-Tyng Li
學位類別:碩士
校院名稱:中原大學
系所名稱:奈米科技碩士學位學程
學門:工程學門
學類:材料工程學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:212
中文關鍵詞:近紅外光紅光細胞遷移骨髓間葉幹細胞低能量光照基質衍生因子
外文關鍵詞:red lightcell migrationlow level light irradiationbone marrow mesenchymal stem cellstroma-derived factornear infrared light
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摘要

間葉幹細胞 (mesenchymal stem cells, MSCs) 能透過血流跨越血管內皮屏障由骨髓遷移至受傷組織,並在受損部位分化成具功能的細胞,因此在再生醫學上扮演重要的角色。趨化素基質衍生因子 (Stroma-derived factor, SDF) -1α在幹細胞遷移至受損或缺氧組織亦具有加乘的效果。本研究目的在探討添加 SDF-1α (SDF) 以及4 J/cm2紅光 (Red) 與近紅外光 (NIR) 低能量光照刺激 (Low level light irradiation, LLLI) 提升大鼠骨髓 MSCs 遷移能力之機制。跨膜遷移試驗得知Red 和 NIR 組的移動細胞數高於控制組。而 SDF+Red 和 SDF+NIR 組與Red 和 NIR 組相比更能顯著提升細胞的遷移能力。此外,C-X-C chemokine receptor type 4 (CXCR4) 的基因和蛋白質表現以及焦點黏附激酶 (Focal adhesion kinase, FAK) 蛋白質磷酸化的表現也明顯提高。利用小干擾 RNA (small interfering RNA, siRNA)轉染大鼠骨髓 MSCs抑制FAK和 CXCR4表現,結果發現轉染 FAK siRNA 和CXCR4 siRNA分別可使細胞遷移降低 41 % 和58 %,無論是LLLI 或 SDF 處理仍無法使細胞遷移回復到與未轉染控制組相同的數目。其中,轉染 FAK siRNA 和CXCR4 siRNA分別可使 pFAK 表現分別降低36 % 和78 %;Red、NIR 和 SDF + Red、SDF + NIR 組的pFAK 表現全部被抑制。然而轉染 FAK siRNA 以及LLLI 或 SDF 處理對CXCR4的表現並無顯著影響。西方墨點法偵測發現 Red、NIR、SDF、SDF + Red 及SDF + NIR 組的phospho-Nuclear factor-κappa B (pNF-κB) p65表現皆明顯提升且會轉位至細胞核內,尤以SDF + NIR 組最為明顯。轉染 FAK siRNA後,無論是 LLLI 或 SDF 處理組的 pNF-κB p65表現均與控制組無差異;而轉染 CXCR4 siRNA 則會抑制所有組別之 pNF-κB p65表現。在基質金屬蛋白酶 (Matrix metalloprotease, MMP)分析方面,明膠分解酶圖譜分析和即時定量聚合酶鏈鎖反應 (Quantitative real-time polymerase chain reaction, QPCR) 結果得知 Red、NIR、SDF、SDF + Red 及 SDF + NIR 組的 MMP-2 活性和基因表現量同樣明顯提高,SDF、SDF + Red 及 SDF + NIR 組的MMP-9 及MMP-14的表現皆高於控制組;而基質金屬蛋白酶組織抑制劑 (Tissue inhibitor of matrix metalloproteinase, TIMP)-2 的基因表現則低於控制組。轉染FAK 和 CXCR4 siRNA 會使 MSCs的 MMP-2活性分別降低 23 及 25 %,而LLLI或SDF處理則會使其活性明顯降低,尤以SDF + NIR 組為甚。在 β1-integrin 及細胞骨架 F-actin表現影響方面,LLLI刺激及SDF誘導會提升β1-integrin 蛋白質的表現。CXCR4 siRNA 轉染 MSCs,會抑制各組之 β1-integrin 表現;轉染 FAK siRNA 則對各組之 β1-integrin表現無顯著影響。螢光染色發現Red、NIR、SDF、SDF + Red 及 SDF + NIR 組的細胞皮層有大量F-actin 聚集情形,亦偵測到其Rac/Cdc42及Rho 蛋白表現增加。在熱休克蛋白方面,QPCR 分析發現 SDF、SDF + Red 及 SDF + NIR 組的HSP27 基因表現分別降低37、25及22 %,Red、NIR、SDF、SDF + Red 及SDF + NIR 組的HSP90 基因表現分別降低62、58、58、71 及 79 %。綜上所述,紅光與近紅外光LLLI刺激和SDF-1α 處理能透過活化CXCR4、FAK及NF-κB的磷酸化、提升MMPs的分泌,進而使F-actin 聚合、增加Rac/Cdc42及Rho 蛋白表現,進而促進大鼠骨髓 MSCs 的遷移。

Abstract

Mesenchymal stem cells (MSCs) play an important role in tissue regeneration which involves the processes of mobilization of stem cells from the bone marrow, homing of these cells to the site of injury, and differentiation of the stem cell into a functional cell of the injured tissue. Stroma-derived factor-1α (SDF-1α) plays a critical role in stem cell migration towards areas of tissue injury and hypoxia. The aim of this study was to examine the influence of low level light irradiation (LLLI) using red and near infrared (NIR) at energy dose on 4 J/cm2 on migration of rat bone marrow MSCs in the absence and presence of SDF-1α (SDF). Results of transwell migration assay showed that the migration of MSCs after Red and NIR light irradiation was greater than control. The migration was further enhanced with SDF-1α treatment. The gene and protein expression of C-X-C chemokine receptor type 4 (CXCR4) and phosphorylation of focal adhesion kinase (FAK) were also enhanced. The expression of FAK and CXCR4 was inhibited by transfecting MSCs with FAK and CXCR4 small interfering RNA (siRNA). MSCs transfected with FAK siRNA and CXCR4 siRNA exhibited decreased cell migration by 41% and 58%, respectively. LLLI or SDF treatment could not recover cell migration capability to the level comparable to that of untransfected control group. MSCs transfected with FAK siRNA and CXCR4 siRNA exhibited decreased pFAK expression by 36% and 78%, respectively. The expression of pFAK was also inhibited in the groups of Red, NIR, SDF, SDF + Red, and SDF + NIR. However, the level of CXCR4 expression was not affected by FAK siRNA transfection, LLLI or SDF treatment. The level of phospho-Nuclear factor-κappa B (pNF-κB) p65 expression was found to increase as shown by western blotting, and nuclear translocation of pNF-κB was observed in the groups of Red, NIR, SDF, SDF + Red, and SDF + NIR, especially in SDF + NIR group. LLLI or SDF treatment did not influence pNF-κB expression in FAK siRNA transfected MSCs. But pNF-κB expression was inhibited in all treatment groups of CXCR4 siRNA transfected cells. As demonstrated by gelatin zymography and quantitative real-time polymerase chain reaction (QPCR) analysis, the activity and gene expression matrix metalloproteinase (MMP)-2 were both elevated in the groups of Red, NIR, SDF, SDF + Red, and SDF + NIR. The levels of MMP-9 and MMP-14 expression of SDF, SDF + Red, and SDF + NIR groups were higher than that of control group, whereas the level of tissue inhibitor of matrix metalloproteinase (TIMP)-2 was lower than that of control group. MSCs transfected with FAK siRNA and CXCR4 siRNA exhibited decreased MMP-2 activity by 36% and 78%, respectively. LLLI or SDF treatment further suppressed MMP-2 activity, especially in SDF + NIR group. β1-integrin expression was upregulated in LLLI and SDF treatment but inhibited by CXCR4 siRNA transfection. There was no significant difference of β1-integrin expression in FAK siRNA transfected cells. The results of fluorescence staining showed that F-actin polymerization accumulated in the cortex of MSCs as well as Rac/Cdc42 and Rho protein expression in Red, NIR, SDF, SDF + Red and SDF + NIR groups. Furthermore, F-actin polymerization was inhibited after transfection of FAK siRNA and CXCR4 siRNA. QPCR analysis found that the expression of HSP27 gene of SDF, SDF + Red and SDF + NIR group decreased by 37, 25 and 22 %, respectively. The expression of HSP90 gene of Red, NIR, SDF, SDF + Red and SDF + NIR group decreased by 62, 58, 58, 71 and 79 %, respectively, compared to that of control group. This suggests that decreased levels of HSP27 and HSP90 might help LLLI and SDF-1α induced cell migration. In summary, LLLI with red and NIR light and SDF-1α treatment could stimulate MSCs motility in vitro through CXCR4 activation, FAK and NF-κB phosphorylation, increasing MMPs secretion, and upregulating F-actin polymerization as well as Rac/Cdc42 and Rho protein expression.

目錄

摘要 I
Abstract III
致謝 VI
目錄…………………………………………………………………………..VII
圖索引 XIII
表索引 XVII
縮寫表 XVIII
第一章 緒論 1
1.1. 前言 1
1.2. 研究動機及目的 2
第二章 文獻回顧 4
2.1. 低能量光照治療之起源 4
2.2. 低能量光照所引發細胞內的訊息傳遞 6
2.2.1. PI3K/Akt 訊息傳導路徑 8
2.2.2. Src/PKC 訊息傳導路徑 9
2.2.3. MAPK/ERK 訊息傳導路徑 10
2.2.4. GSK-3β/Bax 訊息傳導路徑 11
2.3. 間葉幹細胞的治療與應用 12
2.3.1. 趨化素和受器 13
2.3.2. 內源性電場影響 14
2.4. MSCs 遷移引發細胞內的訊息傳遞 14
2.4.1. 細胞遷移機制 14
2.4.2. FAK 訊息傳導路徑 15
2.4.3. MMPs 及 TIMPs 18
2.4.4. proMMPs 的活化 20
2.4.5. HSP27/HSP70/HSP90 20
2.4.6. 骨橋蛋白 22
2.5. 低能量光照促進細胞遷移之作用機制 23
第三章 材料與方法 25
3.1. 紅光與近紅外光 LED 光板組裝 25
3.2. 實驗設計 26
3.3. 低能量光照刺激參數 27
3.4. 細胞分離與培養技術 28
3.4.1. 大鼠來源 28
3.4.2. 麻醉藥配製 28
3.4.3. 紅血球裂解溶液配製 29
3.4.4. 抗凝血劑配製 29
3.4.5. MSCs 分離過程 29
3.4.6. 磷酸鹽緩衝溶液配製 31
3.4.7. MSCs 長期培養基 31
3.4.8. 胰蛋白酶配製 32
3.4.9. 台盼藍染劑配製 32
3.4.10. MSCs 繼代過程 33
3.4.11. 細胞計數 33
3.5. 細胞跨膜遷移能力分析 34
3.5.1. SDF-1α 操作溶液配製 34
3.5.2. 不同濃度 SDF-1α 對 MSCs 遷移能力之影響 35
3.5.3. LLLI 刺激添加 SDF-1α 對 MSCs 遷移能力之影響 .35
3.6. 明膠分解酶圖譜分析 36
3.6.1 焦集膠緩衝溶液製備 36
3.6.2. 分離膠緩衝溶液製備 36
3.6.3. 10 % SDS 溶液製備 36
3.6.4. 0.8 % 明膠溶液製備 37
3.6.5. 10 % APS 製備 37
3.6.6. 7.5 % 聚丙烯胺凝膠製備 37
3.6.6.1. 含 0.1 % 明膠分離膠製備 37
3.6.6.2. 4 % 焦集膠製備 37
3.6.7. 蛋白質電泳緩衝溶液製備 37
3.6.7.1. 3 X 非還原樣本緩衝溶液 37
3.6.7.2. 1 X 電泳緩衝溶液 38
3.6.8. 明膠分解酶圖譜分析呈色藥物配製 38
3.6.8.1. Triton-X100 緩衝溶液 38
3.6.8.2. Tris-HCl 緩衝溶液 38
3.6.8.3. 呈色緩衝溶液 38
3.6.8.4. Coomassie blue 染劑 38
3.6.8.5. 退染溶液 39
3.6.9. 明膠分解酶圖譜分析步驟 39
3.7. 西方墨點法分析 40
3.7.1. 西方墨點法相關藥物配製 40
3.7.1.1. 緩衝溶液 40
3.7.1.2. 1 X TBST 溶液 41
3.7.1.3. 細胞裂解溶液 41
3.7.1.4. 5 % 脫脂奶粉溶液 41
3.7.2. 西方墨點法步驟 41
3.8. 蛋白質定量分析 44
3.9. 免疫螢光染色分析 45
3.10. 螢光染色分析 47
3.10.1. 螢光染色步驟 47
3.10.2. 螢光光譜儀分析 48
3.11. LLLI 刺激添加趨化素 SDF-1α,對相關基因表現之影響 48
3.11.1. 反轉錄聚合酶鏈鎖反應 49
3.11.2. mRNA 的萃取及純化 49
3.11.3. Total RNA 定量 50
3.11.4. 反轉錄作用步驟 50
3.11.5. 聚合酶鏈鎖反應 51
3.11.6. DNA 瓊膠電泳 51
3.11.7. ImageJ 半定量化 52
3.11.8. 即時定量聚合酶鏈鎖反應 52
3.12. 小干擾 RNA 原理及技術 56
3.12.1. 設計雙股 FAK siRNA 和 CXCR4 siRNA 序列 56
3.12.2. 螢光顯微鏡觀察 MSCs 轉染 siRNA 後之轉染效率 58
3.12.3. 流式細胞儀分析siRNA 轉染 MSCs 後之轉染效率 59
3.12.3.1. FAK siRNA 和 CXCR4 siRNA 藥品前處理 59
3.12.3.2. 轉染作用和流式細胞儀分析 59
3.12.4. 西方墨點法分析 siRNA 轉染 MSCs 之蛋白質表現 61
3.12.5. 螢光染色分析 siRNA 轉染 MSCs 之 F-actin 表現 62
3.12.6. 免疫沉澱法 63
3.12.7. ELISA 定量分析 65
3.13. 統計分析 66
第四章 結果 67
4.1. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 遷移能力之影響 67
4.2. LLLI 刺激及添加 SDF-1α 對 CXCR4 和 pFAK 表現之影響 70
4.3. FAK siRNA 和 CXCR4 siRNA 轉染大鼠骨髓 MSCs 74
4.4. LLLI 刺激及添加 SDF-1α 對FAK siRNA 和 CXCR4 siRNA 轉
染大鼠骨髓 MSCs 的遷移能力影響 77
4.5. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 之 MMPs 及 TIMPs 表現的影響 81
4.6. LLLI 刺激及添加 SDF-1α 對 FAK siRNA 和 CXCR4 siRNA 轉
染之大鼠骨髓 MSCs FAK 磷酸化及 CXCR4 的影響 102
4.7. LLLI 刺激及添加 SDF-1α 對促進大鼠骨髓 MSCs pNF-κB 活化
並轉位至核內的表現 109
4.8. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs β1-integrin 表現之
影響 114
4.9. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 的細胞骨架、形態
以及 Rho GTPase 活化之影響 119
4.10. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 熱休克蛋白基因
表現之影響 140
第五章 討論 144
5.1. LLLI 刺激添加 SDF-1α 對大鼠骨髓 MSCs 遷移能力之影響 144
5.2. LLLI 刺激添加 SDF-1α 誘導會活化大鼠骨髓 MSCs 之 pFAK
和 CXCR4 的表現 144
5.3. FAK siRNA 和 CXCR4 siRNA 轉染大鼠骨髓 MSCs 145
5.4. LLLI 刺激及添加 SDF-1α 能雙向誘導大鼠骨髓 MSCs 遷移 145
5.5. LLLI 刺激及添加 SDF-1α 誘導大鼠骨髓 MSCs 分泌 MMPs 146
5.6. FAK siRNA 和 CXCR4 siRNA 轉染大鼠骨髓 MSCs 經 LLLI 刺激及 SDF-1α 處理對 FAK 磷酸化及 CXCR4 表現之影響 149
5.7. LLLI 刺激及添加 SDF-1α 促進大鼠骨髓 MSCs 之 pNF-κB 表現並轉位至核內 150
5.8. LLLI 刺激及添加 SDF-1α 會活化 CXCR4 並經由 NF-κB 磷酸化來調控 β1-integrin 的表現 152
5.9. LLLI 刺激及添加 SDF-1α 可促進細胞骨架 F-actin 聚合、改變細胞形態和活化 Rho GTPase 蛋白 153
5.10. LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 熱休克蛋白基因表現之影響 155
第六章 結論與未來展望 157
參考文獻 166
附錄表 178
A.儀器表 178
B.藥品資料表 180
C.附圖 184









圖索引

圖1-1研究架構 3
圖3-1 LED光板 26
圖 3-2 初代大鼠骨髓 MSCs 的群落形態 34
圖 4-1不同濃度之 SDF-1α 對 MSCs 遷移能力之影響 68
圖 4-2 LLLI 處理及 SDF-1α 添加對大鼠骨髓 MSCs 遷移能力之影響 69
圖 4-3 LLLI 及添加 SDF-1α 對 pFAK 表現之影響 71
圖 4-4 LLLI 及添加 SDF-1α 對 CXCR4 表現之影響 72
圖 4-5 LLLI 及添加 SDF-1α 對 CXCR4 基因表現之影響 73
圖 4-6螢光顯微鏡觀察 FAK siRNA 和 CXCR4 siRNA 轉染大鼠骨髓MSCs 細胞轉染情形 75
圖 4-7流式細胞儀分析 FAK siRNA 和 CXCR4 siRNA 轉染大鼠骨髓MSCs 之轉染效率 76
圖 4-8 LLLI 刺激及添加 SDF-1α 對 FAK siRNA 轉染之大鼠骨髓 MSCs 的細胞遷移能力影響 78
圖 4-9 LLLI 刺激及添加 SDF-1α 對 CXCR4 siRNA 轉染大鼠骨髓 MSCs 的細胞遷移能力影響 80
圖 4-10 LLLI 刺激及添加 SDF-1α 對大鼠骨髓 MSCs 分泌 MMP-2 活性之影響 85
圖 4-11 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs 的 MMP-2 基因表現之影響 87
圖 4-12 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs 分泌 MMP-9 活性之影響 89
圖 4-13 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs 的 MMP-9 基因表現之影響 90
圖 4-14 LLLI 刺激及添加 SDF-1α 對 FAK siRNA 轉染大鼠骨髓 MSCs 所分泌之 MMP-2 活性之影響 92
圖 4-15 LLLI 刺激及添加 SDF-1α 對 FAK siRNA 轉染大鼠骨髓 MSCs 所分泌之 MMP-9 活性之影響 94
圖 4-16 LLLI 刺激及添加 SDF-1α 對 CXCR4 siRNA 轉染大鼠骨髓 MSCs 所分泌之 MMP-2 活性之影響 95
圖 4-17 LLLI 刺激及添加 SDF-1α 對CXCR4 siRNA 轉染大鼠骨髓 MSCs 所分泌之 MMP-9 活性之影響 97
圖 4-18 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs TIMP-1 基因表現之影響
98
圖 4-19 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs TIMP-2 基因表現之影響 100
圖 4-20 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs MMP-14 基因表現之影響 102
圖 4-21 LLLI 刺激及 SDF-1α 處理對 FAK siRNA 轉染之大鼠骨髓 MSCs 的 pFAK 和 CXCR4 表現之影響 104
圖 4-22 LLLI 刺激及 SDF-1α 處理對 CXCR4 siRNA 轉染之大鼠骨髓 MSCs 的 pFAK 和 CXCR4 表現之影響 107
圖 4-23 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs pNF-κB 表現之影響 111
圖 4-24 LLLI 處理及添加 SDF-1α 可增強大鼠骨髓 MSCs pNF-κB 的活化並轉位至核內 112
圖 4-25 LLLI 刺激及添加 SDF-1α 對 FAK siRNA 轉染之大鼠骨髓 MSCs pNF-κB 表現之影響 113
圖 4-26 LLLI 處理及添加 SDF-1α 對 CXCR4 siRNA 轉染之大鼠骨髓 MSCs 的 pNF-κB 表現之影響 114
圖 4-27 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs β1-integrin 表現之影響
117
圖 4-28 LLLI 刺激及 SDF-1α 處理 FAK siRNA 轉染之大鼠骨髓 MSCs 的 β1-integrin 表現之影響 118
圖 4-29 LLLI 刺激及 SDF-1α 處理對 CXCR4 siRNA 轉染之大鼠骨髓 MSCs 的 β1-integrin 表現之影響 119
圖 4-30 LLLI 及 SDF-1α 處理 5 min 後,大鼠骨髓 MSCs F-actin 表現之變化情形 122
圖 4-31 LLLI 及 SDF-1α 處理 15 min 後大鼠骨髓 MSCs 形態之變化情形 124
圖 4-32 LLLI 及 SDF-1α 培養 15 min 後,大鼠骨髓 MSCs 之 Cdc42/Rac 之變化情形..................................................................................128
圖 4-33 LLLI 及 SDF-1α 培養 15 min 後,大鼠骨髓 MSCs 之 Rho 蛋白質之變化情形 132
圖 4-34 LLLI 及 SDF-1α 處理 FAK siRNA 轉染之大鼠骨髓 MSCs 5 min 後 F-actin 表現之變化情形 136
圖 4-35 LLLI 及 SDF-1α 處理 CXCR4 siRNA 轉染之大鼠骨髓 MSCs 5 min 後 F-actin 表現之變化情形 140
圖 4-36 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs HSP27 基因表現之影響
145
圖 4-37 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs HSP70 基因表現之影響
146
圖 4-38 LLLI 處理及添加 SDF-1α 對大鼠骨髓 MSCs HSP90 基因表現之影響 147
圖 6-1 LLLI 處理添加 SDF-1α 雙向誘導 rbMSCs 遷移之機制 163


















表索引

表 3-1 實驗設計及量測時間 27
表 3-2 西方墨點法之抗體濃度稀釋參考表 43
表 3-3 標準曲線之 BSA 濃度稀釋表 44
表 3-4 QPCR 反應組成分配製 53
表 3-5 QPCR 機型 ABI7300 Two-step cycling protocol 53
表 3-6 MSCs 之 PCR 所使用的引子核酸序列及反應參數 54
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