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研究生:范毓珮
研究生(外文):Yu-Pei Fan
論文名稱:移植人類臍帶間質幹細胞治療大白鼠腹膜透析所引起的腹膜纖維化
論文名稱(外文):The Potential Application of the Human umbilical Mesenchymal Stem Cells on Treatment for Peritoneal Dialysis-Induced Fibrosis in Rat
指導教授:傅毓秀傅毓秀引用關係
指導教授(外文):Yu-Show Fu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:115
中文關鍵詞:人類臍帶間質幹細胞腹膜纖維化
外文關鍵詞:Human umbilical Mesenchymal Stem CellsPeritoneal Fibrosis
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腹膜透析是一種腎臟的替代性療法,但長期使用腹膜透析會造成嚴重的併發症-腹膜纖維化 (peritoneal fibrosis)。研究發現透析液中的葡萄糖經代謝後,會產生葡萄糖代謝產物 (glucose degradation product;GDP) - methylglyoxal (MGO),然而進一步將會被誘導產生具有毒性的 advanced glycation end product (AGE)。這些代謝產物已被認為是造成腹膜損傷的重要原因之一。
目前臨床上發現,使用腹膜透析的病人約七至八年即有腹膜纖維化的症狀,此時病人則必須改用血液透析療法。在基礎醫學研究上,一般均採用藥物來抑制腹膜的纖維化,但這些藥物的使用必須考量其是否具有副作用,所以藥物治療腹膜纖維化,仍須在確認與進一步研究。因此,勢必要在尋找另一種更好、更安全、無副作用、又長效的治療方式。
本實驗室先前研究,取存在於人類臍帶瓦頓氏凝膠內的間質幹細胞 (human umbilical cord mesenchymal stem cells in wharton’s jelly,簡稱 HUMSCs) 分化為多巴胺神經細胞,再植入患有柏金森氏症的大白鼠紋狀體內,發現移植後四個月,人類臍帶間質幹細胞仍然存活於大白鼠腦內,不會引起宿主產生免疫排斥反應。此外人類臍帶間質幹細胞是一種生產後的廢棄物,來源取得容易,沒有道德顧慮,處理方式簡單,而且數量極多、繁殖快速的一種幹細胞。因此,認為人類臍帶間質幹細胞為一個適合用來進行異體移植的良好幹細胞來源。本實驗將探討人類臍帶間質幹細胞,治療大白鼠腹膜纖維化的可能性。
首先,體外培養中的人類腹膜間皮細胞 (human peritoneal mesothelial cell;HPMC) 經 serum-free DMEM:4.25% dextrose 透析液 = 1:3 處理 24 小時,人類腹膜間皮細胞形態明顯改變,且藉由流式細胞儀分析後,也觀察到細胞大量受損。人類臍帶間質幹細胞與人類腹膜間皮細胞共同培養,發現可避免人類腹膜間皮細胞受到透析液的傷害。
動物實驗方面,含有 20mM methylglyoxal (MGO) 之透析液打入大白鼠腹腔中,連續三週,使其產生腹膜纖維化,再進行人類臍帶間質幹細胞的移植。結果顯示,PD/MGO 組處理三週後,其腹腔外觀有腹繭生成及腸道肥大現象,並伴隨著體重下降。另一方面,壁層及臟層腹膜均有增厚的情形,且其纖維化的現象明顯增多。同時,利用免疫染色的方法及微正電子斷層掃描 (MicroPET) ,發現發炎情形增加。另外,使用Griffonia simplicifolia 1 (GS1)-lectin 觀察血管新生情況,結果顯示,血管會大量增生。進一步,探討腹膜透析功能是否因給予 PD/MGO 而受損,以腹膜平衡測試發現,PD/MGO 組的腹水體積及腹水中的 glucose 濃度均明顯減少,而腹水中 creatinine 明顯增加,顯示其腹膜透析功能有降低之情況。
我們將1x107 之人類臍帶間質幹細胞植入於大白鼠腹腔,移植後三週,其腹腔外觀之腹繭現象消失,且體重有逐漸上升之趨勢。另外,其腹膜增厚及纖維化現象的情形有統計降低的現象。另一方面,幹細胞移植組,其腹腔內發炎反應與血管增生和 PD/MGO 組相比,顯著降低。此外,幹細胞移植組,其腹膜透析功能也明顯回復。
最後,以 anti-human specific nuclei antigen 組織免疫染色結果呈現,植入人類臍帶間質幹細胞三週後,HUMSCs 之細胞核仍存在於腸的膜上,並未受到排斥。再以 MicroPET 影像顯示,植入人類臍帶間質幹細胞於大白鼠腹腔三週及八週後,大白鼠的腹腔並未偵測到腫瘤的生成。
綜合細胞及動物實驗結果顯示,人類臍帶間質幹細胞的移植,有助於腹膜纖維化的修復。推測修復機制為人類臍帶間質幹細胞長時間存在於受損的腹腔中,而可能釋放出生物激素,以達到改善效果。
Continuous ambulatory peritoneal dialysis is a well-accepted treatment for end-stage renal disease. Peritoneal fibrosis is a major complication of long-term peritoneal dialysis (PD). The involvement of peritoneal structural and functional changes, predominantly in the submesothelial compact collagenous zone, membrane hyperpermeability, and ultrafitration failure.
Glucose degradation products contained in peritoneal dialysis solution contribute greatly to the bioincompatibility of commercial peritoneal dialysis solution, such as methylglyoxal (MGO) and are risk factors for peritoneal fibrosis.
Stem cells, believed to possess certain characteristics including self-renewal, pluripotency, proliferation, longevity and differentiation. We have shown that human umbilical mesenchymal cells in Wharton's jelly (HUMSCs) possess stem cell properties.
HUMSCs can be easily obtained and processed, compared to embryonic and bone marrow stem cells. We also found that the transformed HUMSCs in the striatum were still viable 4 months after transplantation without the need for immunological suppression, suggesting that HUMSCs might be a good stem cell source for transplantation.
In vitro, our results showed that the human peritoneal mesothelial cells (HPMC) damaged in peritoneal dialysis solution, and HUMSCs prevented this injury.
In the animal model, we used the male Sprague-Dawley rats that were treated (1) normal saline, (2) 4.25% dextrose PD solution, (3) 4.25% dextrose PD solution containing 20 mM MGO (PD/MGO), and (4) 4.25% dextrose PD solution containing 20 mM MGO with HUMSCs (PD/MGO with HUMSCs) every day for 3 weeks.
In this study, we investigated the effect of HUMSCs transplanted into established peritoneal fibrosis. HUMSCs were transplanted into abdomen, rats had significantly reduced PD/MGO-induced peritoneal fibrosis, as assessed by thickening of the membrance, sirius red staining, and collagen content assay of the peritoneum, compared to those of rats treated with the PD/MGO group. The body weight and peritoneal function showed significantly higher in the PD/MGO with HUMSCs group. In immunohistochemistry, expression of α-SMA and ED1 were significantly suppressed by transplantation. Moreover, we observed neoangiogenesis in the PD/MGO with HUMSCs group that were lower than the PD/MGO group. As shown by MicroPET imaging, no tumor and decreased inflammation was detected in the abdomen 3 and 8 weeks after the transplantation of HUMSCs.
According to our research, transplantation may provide a new approach to reduce peritoneal fibrosis.
中文摘要 1
英文摘要 4
第一章 緒論 7
1.1 腹膜透析 7
1.1.1 腹膜透析的優點 8
1.1.2 腹膜透析的缺點 8
1.2 腹膜纖維化的發生機轉 9
1.3 腹膜纖維化的動物模式 11
1.4 治療腹膜纖維化的基礎醫學研究 12
1.5 幹細胞修復臟器纖維化的基礎醫學研究 13
1.5.1 幹細胞與腎臟纖維化 13
1.5.2 幹細胞與肝臟纖維化 14
1.6 幹細胞移植 15
1.6.1 胚胎幹細胞 15
1.6.2 臍帶血幹細胞 16
1.6.3 骨髓幹細胞 16
1.7 人類臍帶間質幹細胞 17
第二章 實驗目的 20
第三章 材料與方法 21
3.1 人類臍帶間質幹細胞之體外培養 21
3.2 人類腹膜間皮細胞之體外培養 21
3.3 腹膜透析液的處理 23
3.3.1 以倒立式光學顯微鏡觀察形態 23
3.3.2 以流式細胞分析儀分析細胞受損的情形 23
3.4 實驗動物 24
3.5 腹腔內埋管 24
3.6 腹膜纖維化的大白鼠模式建立 25
3.7 實驗分組 25
3.8 人類臍帶間質幹細胞移植 26
3.9 實驗動物犧牲、灌流固定、與冷凍切片 27
3.10 蘇木紫-伊紅染色 (Hematoxylin & Eosin Stain,簡稱 H&E Stain) 28
3.11 組織纖維化染色 (Sirius Red Stain) 28
3.12 組織免疫染色 29
3.13 腹膜血管的測量 30
3.14 微正電子放射電腦斷層攝影 (Micro-Positron Emission Tomography,簡稱 MicroPET) 31
3.15 西方墨漬法 (Western Blot) 32
3.15.1 蛋白質萃取 32
3.15.2 蛋白質濃度測試 32
3.15.3 電泳 (Electrophoresis) 33
3.15.4 西方墨漬法 (Western blot) 34
3.15.5 影像截取計算 35
3.16 可溶性膠原纖維測量 (Soluble Collagen Measurement) 35
3.17 腹膜平衡試驗 (Peritoneal Equilibration Test,簡稱 PET) 36
3.18 統計分析 (Statistical Analysis) 37
第四章 結果 38
4.1 高糖透析液並不會造成體外培養中的人類臍帶間質幹細胞的損傷 38
4.2 高糖透析液會導致體外培養中的人類腹膜間皮細胞受損 38
4.3 與人類臍帶間質幹細胞共同培養下的人類腹膜間皮細胞,經高糖透析液處理後,細胞受損比例降低 39
4.4 移植人類臍帶間質幹細胞,避免腹繭的生成 39
4.5 移植人類臍帶間質幹細胞,抑制壁層腹膜的增厚 41
4.6 移植人類臍帶間質幹細胞,阻止臟層腹膜的增厚 42
4.7 移植人類臍帶間質幹細胞,避免壁層腹膜纖維化的增多 43
4.8 移植人類臍帶間質幹細胞,阻止臟層腹膜纖維化的增加 44
4.9 移植人類臍帶間質幹細胞,可降低腹膜的發炎反應 46
4.10 移植人類臍帶間質幹細胞,減緩腹膜內血管的增生 47
4.11 以微正電子斷層掃描顯示,移植人類臍帶間質幹細胞可抑制腹腔內的發炎反應 48
4.12 移植人類臍帶間質幹細胞,可修復腹膜透析的功能 49
4.12.1 腹水體積 (Drain volume) 49
4.12.2 葡萄糖濃度變化 (D4/D0 glucose) 50
4.12.3 肌酸酐濃度變化 (D4/P4 creatinine) 50
4.13 人類臍帶間質幹細胞存活於大白鼠腹腔中 51
4.14 移植人類臍帶間質幹細胞不會形成腫瘤 51
第五章 討論 52
5.1 高糖透析液誘發人類腹膜間皮細胞的死亡 52
5.2 葡萄糖代謝產物造成腹膜組織的變異 53
5.2.1 巨觀形態及生理變化 53
5.2.2 纖維化現象 54
5.2.3 發炎反應 55
5.2.4 血管新生 56
5.3 植入人類臍帶間質幹細胞能有效降低腹膜纖維化 56
5.4 植入人類臍帶間質幹細胞減低腹膜纖維化之可能機制 58
5.5 結論與未來展望 59
第六章 參考文獻 60
第七章 圖表 70
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