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研究生:沈炯祺
研究生(外文):Chiung-Chyi
論文名稱:內源性幹細胞自我拯救和外源性幹細胞治療大鼠缺血性中風之相關分子機轉之探討
論文名稱(外文):The molecular mechanisms for endogenous stem cell self-rescue and exogenous stem cells therapy in ischemic stroke rats
指導教授:柯俊良柯俊良引用關係
指導教授(外文):Jiunn-Liang Ko
學位類別:博士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:71
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本研究主要探討內源性幹細胞與外源性添入之神經幹細胞對於缺血性腦中風之神經保護特性與相關治療機轉。近年來,幹細胞相關研究已成為神經修復與神經再生的熱門標的,研究顯示幹細胞具有分化潛能,在器官組織受到傷害時,能給予適當的支援與修補,甚至分化、再生和取代。因此,本研究利用大白鼠中大腦動脈缺血性中風-再灌流的動物模式,探討內源性幹細胞在中風後,其來源分佈及時間周期情形,對於自我修復與神經保護之貢獻,之後再使用從胎鼠前腦所分離出來的神經幹細胞給予細胞治療,評估此類治療在中風後之神經保護和行為恢復之治療效益,並深入了解可能參予分子是透過何種機轉來保護腦細胞。
首先本研究利用大白鼠進行中大腦動脈縫線栓塞手術,再進行灌流(ischemia - reperfusion)實驗,希望能模擬中風患者經血栓溶解治療後之大腦組織的變化;缺血性中風後一小時後,雖然馬上執行血液再灌流,但是大鼠大腦已經造成不可逆之缺血性損傷,經過神經損傷分級判定,損傷2~3級之中風大白鼠為實驗分析對象;經TTC染色分析得知中風後腦損傷面積與腦萎縮比例,腦損傷面積在中風後1~3天可達最大值,約佔全腦面積25%;在中風後7天大腦開始萎縮,約佔半腦的5%,中風後14~28天後,大腦萎縮比率穩定,約呈現佔半腦的10%不等。而現今研究常將nestin視為幹細胞標分子的其中之一,因此本實驗初步以此分子作為探討內源性幹細胞之標的。利用免疫轉漬方式對於中風後的大鼠大腦組織蛋白進行分析,發現nestin明顯被大量誘導表現在中風後3天的中風損傷處(cortex)和中風損傷周邊(striatum),此結果可持續至中風後14天,但在中風後28天僅存大腦皮質有剩餘表現,顯示類幹細胞會經由中風被誘導出來,但其來源和分布情況,尚不明確,因此利用免疫染色觀察nestin cells在中風大腦組織切片中所分佈的情況,結果發現nestin訊號在中風後三天大量出現在腦室周邊(ventricle)(受傷區域的週邊)、紋狀體(striatum)和大腦皮質(cortex)(缺血受傷區域),在中風後七天,大量的nestin細胞形成明顯的nestin boundary,介於中風傷害側與未受傷區域之間,其分佈情況從運動皮質區經由紋狀體區,一直延伸至顆粒層下方;但是在中風後的第14天,出現nestin訊號的範圍縮小,只限制於腦室、紋狀體周邊和olfactory tubercle,在中風28天後,與免疫轉漬結果相同,僅剩下中風側的大腦皮質受傷區域有表現;文獻指出幹細胞本身具有較強的增生特性,因此利用BrdU標定觀察中風後大鼠大腦新生細胞分佈情況,結果顯示僅在中風後3天的大腦中風側邊發現明顯的細胞增生情況,大部份存在於cortex、striatum和olfactory tubercle區域,而在中風7天以後的新生細胞明顯少很多,顯示nestin細胞並非全由新生細胞而來的。而中風組的行為評估,無論是前肢抓力或跑步行為,在7~28天後皆呈現3~4成的行為衰退(相較於假手術組),顯示自我拯救的內源性幹細胞對於中風後的恢復是有限的,即使在中風後3天大腦中風側出現大量的nestin訊號,因此推測這些訊號並非真正的幹細胞訊號,於是選用另一個幹細胞標定分子PSA- NCAM (Polysialic acid-neural cell adhesion molecule),以免疫轉漬方式分析,結果其表現量相較於nestin表現如預期般少很多,顯示真正的內源性幹細胞的恢復效果是明顯不足。
此外,本研究利用外源性幹細胞治療中風大鼠,觀察中風後大腦損傷程度和評估其行為和恢復情況。外源性幹細胞是從胎鼠前腦分離出來,在體外的血清培養下,自我分化實驗可分化成神經元和星狀膠細胞。大白鼠經栓塞1小時再灌流後,待三小時後將外源性幹細胞標定CM-DiI並經由腹股溝靜脈注入中風大鼠體內,經過體內循環遷移大腦受損區域,在7天可達標定的幹細胞數量的最大值,且明顯集中在中風側的striatum,利用TTC染色證實,無論是大腦損傷面積或是萎縮比例,治療組皆比中風組損傷小;前肢抓力行為評估則顯示,經過幹細胞治療的大鼠中風後7~14天的抓力是明顯優於未治療組(P<0.01),具統計意義,在中風後28天後,治療組其抓力仍具有恢復能力,顯示外源性幹細胞治療有一定程度的保護,但並不能代表在長時間的情況下,能持續保護大腦不受中風損傷,日後可思考調整成連續給予幹細胞治療的療程。而深入探討給予幹細胞治療中風可能改善之分子機轉,發現致發炎因子COX-2和IL-1β會在給予幹細胞治療後,其表現量會明顯下降,而保護蛋白Hsp27(Heat shock protein 27)也會在治療組中風後三天明顯的被誘導出來,可保護神經細胞,增強腦細胞對抗中風後所引起細胞凋亡傷害的能力。
因此,本實驗研究結果證明內源性與外源性幹細胞對於中風後的救治能力與分子變化,內源性幹細胞對於中風之保護或修復能力明顯不足,而外源性幹細胞雖然具有保護能力,但也只能提供暫時性的保護,希望將來能多了解中風的分子機轉與治療方式並搭配其他生長因子(例如GDNF、BDNF、G-CSF等)合併使用,並能提供更完整的闡述與應用。

This study focused on endogenous and exogenous stem cells transplanted in the neural stem cells for ischemic stroke of neuroprotective properties associated with the treatment mechanism. In recent years, stem cell research has become the nerve repair and nerve regeneration of the popular subject of studies have shown that stem cells have the potential to divide, in harm organs, can be given appropriate support and repair, and even division, and replaced by renewable sources. As a result, this study using rats in the brain artery ischemic stroke reperfusion animal model to explore the endogenous stem cells in stroke, the source of their case distribution and cycle time for self-repair and neural contributions to the protection, and then from the use of before the fetal rat brain by the isolated neural stem cells to give cell treatment, evaluation of such treatment after a stroke in nerve protection and restoration of acts of effective treatment and may participate in an in-depth understanding of the elements is the means through which the elements of the mechanism.
In this study, first of all rats in the brain artery embolization surgical sutures and then reperfusion (ischemia - reperfusion) experiment, hoping to simulate a stroke after thrombolytic therapy in patients after brain tissue changes; ischemic stroke after an hour later, though immediately the implementation of blood reperfusion, but rats have caused irreversible brain of ischemic injury after nerve defect classification determined that 2 to 3 defects in rats for experimental analysis of the wind objects; by TTC staining was informed analysis of the stroke and brain injury area Brain shrinkage ratio of brain damage after a stroke in the area of 1 to 3 days up to the maximum, accounting for about 25% of the whole area of the brain; 7 days after the stroke in the brain begins to shrink, accounting for about half of the 5% of the brain, a stroke after 14 to 28 days , Brain atrophy rate stability, has accounted for about half the brain of 10%. The current study will be regular stem cells Nestin as one of the standard elements, so this experiment as a preliminary to explore the elements of endogenous stem cells of the subject. The use of immune to stain the way for a stroke after the protein in rat brain tissue for analysis and found that nestin was obviously a large number of induced stroke in 3 days after the stroke injury agency (cortex) and stroke, peripheral damage (striatum), the results of the stroke to sustainable After 14 days, 28 days after the stroke in the left cerebral cortex has a surplus of performance, type of stem cells will be displayed by the stroke was induced, but its source and distribution, is not yet clear. So the use of immune staining nestin cell in the brain tissue of stroke.
Slice in the distribution, nestin is found in a large number of strokes after three days in the neighboring ventricle, striatum and the cerebral cortex were injured in the region in seven days after the stroke, a large number of nestin cell to form a clear nestin boundary. In the range of stroke damage did not side with the injured region, the distribution of its movement from the cortex through the striatum, has been extended to the bottom of the particle layer; but after a stroke in the first 14 days, there nestin Signals in both the scope and restricted to only the ventricle, the striatum and the surrounding olfactory tubercle, in a stroke 28 days after immunization with the results of the stain to the same, only a stroke left side of the cerebral cortex were injured in the region have shown; literature that stem cells themselves have more Strong proliferative properties, the use of BrdU demarcation of the observation post-stroke newborn rat brain cells, showed that only 3 days after the stroke of the large side stroke found that the cells significantly, the majority present in the cortex, striatum and olfactory tubercle region, and in 7 days after the stroke of the new cells significantly less, showing not nestin cells by cells from newborn. The stroke group to assess the conduct, whether running or forelimb grasp, in 7 to 14 days there was a slight recovery and enhance the value, but 28 days after the show are 3 to 4 percent of the recession, show self-rescue of endogenous stem cells for stroke recovery is limited, even in the 3-day-old stroke after stroke side of a large number of nestin signal, so that these signals are not true stem cell signal, then choose another stem cell demarcation of the molecular PSA-NCAM (Polysialic acid-neural cell adhesion molecule), immuno-blot analysis of the way, the results of its performance compared to the amount of nestin expression as expected a lot less of what a truly endogenous stem cells to restore the effect is less obvious.
In addition, the study of the use of exogenous stem cell treatment of stroke in rats to observe the extent of brain damage after a stroke and to assess their conduct and to restore the situation. Exogenous stem cells from fetal rat brain before the separation, the serum in vitro cultivation of self-differentiation into neurons can be divided into experimental and stellate cells in plastic. After 1 hour rats embolism reperfusion after three hours will be derived stem cells outside the demarcation of the CM-DiI and groin by intravenous injection of stroke rats, after a cycle of migration in the body of the brain regions damaged in the calibration of up to 7 days The maximum stem cells, and the apparent stroke on the side of the striatum, the use of TTC staining confirmed that both the area of the brain injury or shrinking proportion of the treatment group than in both stroke damage in small groups; forelimb grip behavioral assessment showed that after stem cell treatment After the stroke in rats 7 to 14 days to grasp the power is better than the untreated group (P <0.01), with statistical significance, but in a stroke within 28 days after the treatment group grasp its power is still about a recession as two shows that foreign although stem cell therapy to a certain degree of protection, but do not represent in a long time, to protect the brain from stroke damage the function of thinking can be adjusted in the future as stem cell therapy in a row to give the course of treatment. And give in-depth study stem cell treatment of stroke may improve the molecular mechanism and found that inflammation-induced COX-2 and IL-1β will be given stem cell treatment, the performance of its volume will be decreased, and the protection of the protein HSP27 (heat shock protein 27 ) Will be treated for three days after the stroke was induced obvious, can protect nerve cells, able to bear the increase in apoptosis injury. Therefore, this experimental study has established that endogenous and exogenous stem cells for the treatment of stroke and the ability to Molecular changes in the future for the molecular mechanism of stroke and treatment methods can provide a more complete set of applications.

目錄
壹、中文摘要 6
貳、英文摘要 8
参、前言 11
一、腦中風症狀 11
二、腦中風的危險因子 12
三、腦中風的預防 12
四、腦中風的治療 13
五、神經幹細胞 14
六、幹細胞治療缺血性腦中風 15
七、研究動機 18
肆、研究材料與方法 19
一、細胞培養 19
二、神經幹細胞篩選和體外鑑定 19
三、Western blotting(西方墨點轉漬法) 20
四、建立大鼠腦缺血再灌流損傷之中風動物實驗模式 22
五、細胞移植 24
六、神經缺陷行為測試與訓練 24
七、動物犧牲及檢體處理 25
八、冷凍切片以及免疫染色 26
九、統計學分析 26
伍、實驗結果
一、缺血性腦中風對於大鼠大腦損傷之評估 27
二、行為測試與神經缺陷分級評估缺血性腦中風之大鼠 27
三、缺血性中風引發大量的nestin細胞表現 28
四、Nestin訊號的分佈區域和出現的時間週期 28
五、BrdU訊號(新生細胞)在中風後分佈的情形 28
六、動物行為評估大鼠在中風之後恢復的程度與其他幹細胞分子之偵測 29
七、神經幹細胞的分離、培養與分化 29
八、神經幹細胞的標定與注入中風大鼠後的分佈情形 29
九、神經幹細胞治療對於中風大鼠的初步觀察與影響 30
十、評估神經幹細胞治療對於中風大鼠的癒後恢復的狀況 30
十一、探討幹細胞治療中風大鼠恢復效果較佳之可能參與的分子機轉 31
陸、討論 33
柒、結論 37
捌、附表與圖表 38
玖、參考文獻 63
拾、已發表之文獻 72

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