臺灣博碩士論文加值系統

糖尿病長年佔據國人十大死因之前五名，幹細胞療法是目前治癒糖尿病具前景的方式之一，然而目前細胞治療糖尿病之臨床試驗效果仍有限。脂肪間質幹細胞具有安全容易取得、可體外放大培養、多能性分化能力和分泌多種細胞激素之優勢，是糖尿病細胞療法的理想來源之一。故本研究以脂肪間質幹細胞為題材，探討其應用於治療糖尿病之可行性。本研究分為三部分：第一，改良產婦腹部塊狀脂肪組織間質幹細胞體外的分離與培養方法，並研究此來源的脂肪間質幹細胞相關特性。第二，於體外人類脂肪間質幹細胞培養出可以產生胰島素的細胞，並以動物模式證明它們是具有治療糖尿病潛力的細胞。實驗結果顯示將脂肪幹細胞移植入以鏈佐黴素與菸鹼醯胺所誘導的糖尿病小鼠體內後，分別都兩劑的中劑量 (4×107 cells/kg) 與高劑量 (8×107 cells/kg) 組別，採間隔兩週靜脈注射為安全且具有較佳療效，並於誘導之糖尿病小鼠體內可顯著降低血糖值，也由免疫組織化學染色法發現表現人類專一性粒線體和胰島素製造細胞可存活在小鼠胰臟內並分化成胰島素分泌細胞。第三，近期文獻發現棕色脂肪細胞具有調控糖代謝的功能，其脂聯素表現也高於白色脂肪細胞，而脂聯素受體又與糖尿病阻抗性相關；本研究篩選可以增加脂聯素基因表現的小分子化合物，發現增加脂聯素表現藥物可以增加類棕色脂肪相關基因的表現，並探討脂肪幹細胞脂聯素的基因表現對治療糖尿病小鼠降血糖療效之影響。本研究結果提供之資訊可作為未來開發幹細胞治療糖尿病患者的臨床應用之基礎。

Diabetes has been one of the top five causes of death in Taiwan for many years. Stem cells provide a promising expectancy for diabetes treatment; however, the efficacy in clinical trial still presents room to improve. Mesenchymal stem cells can be obtained safely and easily from fat tissue, be expanded in vitro with multipotent differentiation ability, and secrete a variety of cytokines. It is therefore that human adipose-derived stem cells (hADSCs) were selected to explore their application for diabetes therapy in this study. In the first part of this study, we aimed to develop a simple method to process adult stem cells from human adipose tissue harvested from the subcutaneous fat of the abdominal wall during gynecologic surgery, and to investigate the characteristics of these cells. In the second part, we examined the efficacy of transplanting hADSCs in diabetic mice. We observed that the middle dosage (4×107 cells/kg) and high dosage of hADSCs (8×107 cells/kg) administered through the tail vein of the diabetic mice would reduce their fasting blood glucose levels. The infiltration of immune cells into pancreatic tissues was reduced and the damage of the islet cells was ameliorated in the hADSC-transplanted mice compared with those of the control group. In addition, pancreatic function was recovered significantly according to biochemical analyses of insulin and glycated hemoglobin levels. Human-specific mitochondria and insulin were observed in pancreatic tissues, indicating that hADSCs differentiated into insulin-producing cells in vivo. Because the expression level of adiponection in brown or white fat cells are relevant to the regulation of glucose metabolism and adiponectin receptors are related to insulin resistance, small molecule compounds that may induce adiponectin gene expression in hADSCs were screened in the last part of this study. The effect of these small molecules on the expression of brown fat-related genes and the reduction on the hyperglycemia in the diabetic mice were examined. The information provided by this research may shed light on the development of future diabetes clinical treatment practice.

一、前言 1
二、研究背景 3
1. 糖尿病介紹 3
2. 幹細胞在糖尿病治療的應用現況 4
3. 脂聯素之相關研究 6
4. 脂肪幹細胞體外分化成類棕色脂肪細胞 9
5. 幹細胞體外分化成胰島素分泌細胞 11
6. 糖尿病動物模式與選擇 13
7. 脂肪來源幹細胞治療糖尿病之臨床試驗 16
三、 材料與方法 19
1. 脂肪間質幹細胞來源 19
2. 脂肪幹細胞鑑定分析 19
3. 幹細胞分化能力分析 20
4. 脂肪間質幹細胞體外分化胰島素分泌細胞 21
5. 反轉錄聚合酶連鎖反應(RT-PCR)與膠體分析 22
6. 體外分化類棕色脂肪細胞 (Brite/Beige cell) 22
7. 双硫腙(Dithizone, DTZ) 染色 23
8.高糖環境影響胰臟相關細胞株的存活 24
9. 西方墨點法 24
10. 免疫細胞螢光染色 25
11. 實驗動物照護與飼養 25
12. 以STZ-NA 誘導非肥胖型糖尿病動物模型 25
13. 細胞移植治療 26
14. 實驗動物採血、血中葡萄糖、膽固醇與三酸甘油酯測定 27
15. 組織處理以及切片 27
16. 蘇木素-伊紅染色 (H&E Stain) 28
17. 免疫化學染色 28
18. 葡萄糖耐受性試驗 29
19. 酵素連結免疫分析法 29
20. 統計分析 29
四、 研究結果 31
1. 剖腹產塊狀脂肪幹細胞分離與培養技術的探討 31
1.1 一般傳統手工的切割法 31
1.2 不同層的塊狀脂肪幹細胞貼附型態觀察 33
1.3 不同層的塊狀脂肪幹細胞生長差異 33
1.4 不同層的塊狀脂肪間質幹細胞的表面抗原分析 34
1.5 不同層的塊狀脂肪間質幹細胞之分化能力測試 36
2. 使用均質機處理脂肪組織的方法 37
2.1比較手工切割與均質機不同條件下對於脂肪檢體SVF量之影響 37
2.2 比較酵素不同處理時間對於脂肪檢體SVF量之影響 37
2.3 均質機程序分離之脂肪間質幹細胞的表面抗原分析 41
2.4 均質機程序分離之脂肪間質幹細胞的細胞生長曲線 42
2.5 均質機程序分離之脂肪間質幹細胞的分化能力 43
3 NA-STZ化學性誘導之糖尿病鼠模式建立 44
3.1脂肪幹細胞移植治療糖尿病小鼠具有改善空腹血糖值之成效 45
3.2 脂肪幹細胞治療降低糖尿病鼠糖化血色素與增加小鼠胰島素分泌 47
3.3 脂肪幹細胞改善糖尿病小鼠的血糖耐受性 48
3.4 脂肪幹細胞改善糖尿病小鼠飲水量與排泄量的生理現象 49
3.5 脂肪幹細胞治療具有修復胰臟組織的功效 50
3.6人類脂肪幹細胞於糖尿病鼠活體內追蹤 51
3.7人類脂肪幹細胞於糖尿病鼠體內之功能性分佈 51
4. 探討體外高糖環境對於脂肪幹細胞之影響 53
4.1 脂肪幹細胞具有較高的脂聯素(adiponectin)基因表現 54
4.2 比較不同脂聯素表現之脂肪幹細胞的硬骨與脂肪分化能力 55
4.3不同脂聯素(adiponectin)表現之脂肪幹細胞類胰島細胞的分化能力 57
4.4探討不同化合物對脂肪幹細胞進行類棕色脂肪細胞分化之影響 58
4.5 以藥物TW01預處理後會增加脂肪幹細胞脂聯素表現 60
4.6 以藥物預處理後的脂肪幹細胞應用於小量糖尿病鼠實驗結果 61
五、討論 63
六、結論 71
七、未來展望 73
八、參考文獻 75

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