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研究生:黃猷智
研究生(外文):You-Jhih Huang
論文名稱:移植人類臍帶間質幹細胞結合DcR3治療大白鼠缺血/再回流傷害所引起之腦梗塞
論文名稱(外文):Combining Human Umbilical Mesenchymal Stem Cell in Wharton’s Jelly with DcR3 for The Treatment of Ischemia/Reperfusion Stroke of 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:112
中文關鍵詞:人類臍帶間質幹細胞缺血/再回流腦中風
外文關鍵詞:Human Umbilical Mesenchymal Stem CellIschemia/Reperfusionstroke
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中文摘要
腦中風 (stroke) 高居國人第二大死因,更是老年人最常見的神經疾病之一。腦中風是因為腦部血管出現局部性的堵塞或出血,使腦組織受到損傷,造成神經細胞損傷或死亡,導致感覺、或運動上不可回復性的缺失,影響行為、情緒表達與生活品質。到目前為止,並沒有任何一種藥物服用後,可以使腦中風患者大幅康復。近年來,隨著幹細胞研究的興起,許多學者開始嘗試移植幹細胞到受損的腦區,期望能達到修復的效果。臍帶為生產後的餘物,容易取得;存在於臍帶 Wharton’s jelly 內的臍帶間質幹細胞 (human umbilical cord mesenchymal stem cells in wharton’s jelly,簡稱 HUMSCs),具有幹細胞的潛能,分離方法簡易。由先前實驗已證明,人類臍帶間質幹細胞不會引起宿主產生免疫排斥反應。之前我們實驗室,取人類臍帶間質幹細胞移植到腦中風之大白鼠大腦皮質內,結果顯示,能夠改善腦中風大白鼠的運動能力到正常時的 70 % 左右,為了更促進運動功能的修復,我們希望在腦中風早期,除了移植人類臍帶間質幹細胞之外,並同時,給予 Decoy receptor 3 (DcR3),期望對腦中風有所幫助。DcR3 是 soluble receptor for CD95 Ligand,可以和 Fas ligand 與 Light 結合後,有效中和神經細胞的死亡,並有效調節發炎反應。本實驗目的,是希望移植人類臍帶間質幹細胞,合併使用 DcR3,來探討治療大白鼠腦中風之可能性與應用價值。
腦中風模式是將每一隻大白鼠的右側大腦中動脈進行 90 分鐘的結紮 (Middle Cerebral Artery Occlusion) 與再回流手術。實驗大白鼠分為四組,第一組為控制組 (Control),大白鼠施予缺血與再回流手術,並在手術後,未經過任何治療。第二組為 DcR3 處理組 (DcR3),大白鼠除了施予缺血與再回流手術,並在手術後,連續三天,每天給予 2 �慊 DcR3 治療。第三組為幹細胞移植組 (HUMSCs),大白鼠除了施予缺血與再回流手術,並於手術後一天,植入 5x105 人類臍帶間質幹細胞。第四組為幹細胞與 DcR3 合併組 (HUMSCs+DcR3),即大白鼠除了施予缺血與再回流手術,並在手術後,連續三天,每天給予 2�慊 DcR3 治療,同時於手術後一天,植入 5x105 人類臍帶間質幹細胞。首先,以 Triphenyl Tetrazollium Chloride (TTC) 染色來檢測大腦皮質損壞的範圍,結果發現,DcR3 組與 (HUMSCs+DcR3) 合併組的大白鼠,其大腦皮質在手術三天後,與未治療的 Control 組相比,損壞範圍有明顯減少的情形。進一步,使用腦部核磁共振造影 (Magnetic Resonance Imaging),連續觀察大白鼠腦部的損傷變化,結果顯示,不論是否有接受治療,大白鼠在手術後第二天內,大腦皮質均會呈現發炎水腫現象,然而,DcR3 組與 (HUMSCs+DcR3) 合併組的大白鼠,其大腦皮質水腫的情形,較未治療的Control組為小。在手術後第九天,梗塞大腦皮質開始出現萎縮現象,但 DcR3 與 (HUMSCs+DcR3) 合併組之皮質萎縮情況與 Control 組相比,有明顯減少的情形 (p<0.05)。隨著時間增加到手術後三十七天,Control組大白鼠的梗塞皮質呈現壞死與萎縮的情形。而 DcR3 組與 (HUMSCs+DcR3) 合併組的大白鼠,則保留較多的梗塞皮質。利用 Cresyl violet 與 anti-NeuN 組織免疫染色觀察也發現,不論是在手術三天、或三十七天後,DcR3 組與 (HUMSCs+DcR3) 合併組的大白鼠,其發炎皮質與受損腦組織內,所含有的神經細胞數目較 Control 組為多。另一方面,DcR3 組與 (HUMSCs+DcR3) 合併組的大白鼠,其梗塞皮質內 GFAP 及 ED1 positive cell 的表現量比 Control 組少,表示大腦皮質內的發炎現象有減緩的現象。
為了進一步證明,存在於受損皮質內神經細胞的活性功能,以氟-18去氧葡萄糖以靜脈注射方式給予大白鼠,以正電子放射電腦斷層掃瞄攝影 (positron emission tomography) 觀察神經細胞的活性變化,結果發現,在手術後三天、或三十七天後,DcR3 組梗塞皮質內神經細胞活性和 Control 組相比,有明顯增加情形 (p<0.05);然而 (HUMSCs+DcR3) 合併組的受損皮質內,神經細胞活性又較 DcR3 組,顯著高出了許多 (p<0.05)。為了定量受損大腦皮質內血管的數目,取 FITC-dextran 灌流大白鼠以標定血管,結果呈現,單獨給予 DcR3,其大腦皮質內血管密度較 Control 組多 (p<0.05);然而 (HUMSCs+DcR3) 合併組的血管數目,與 DcR3 組相比,又呈現明顯的增加情形 (p<0.05)。進一步,定量大白鼠使用大腦受損對側前肢的比例,在結紮手術後一天,單獨處理 DcR3 組別的大白鼠,其行為能力高於 Control 組 (p<0.05)。到手術三天後,單獨處理 DcR3 組、與單獨移植 HUMSCs 組之大白鼠,它們的運動能力都比 Control 組較為改善 (p<0.05);而 (HUMSCs+DcR3) 合併組的行為指數,又較單獨處理 DcR3、或單獨移植 HUMSCs 的組別,呈現明顯的增加情形 (p<0.05),且此趨勢,一直維持到第三十七天。接著,進行 Anti-human specific nuclei antigen 組織免疫染色,可發現在手術三十七天後,仍偵察到人類臍帶間質幹細胞存活在大白鼠受損大腦皮質內。
綜合我們的實驗結果推測,移植人類臍帶間質幹細胞結合 DcR3 能增加受損腦區的血管新生,有效保護梗塞皮質,避免皮質萎縮壞死,並且,增加神經細胞的活性、降低發炎反應,進而增進運動行為的能力,對臨床缺血性腦中風提供一個新的治療方向。
英文摘要
Stroke is a leading cause of death and disability, but despite intensive research only a few treatment options exist. One promising strategy for the treatment of stroke is transplantation of stem cells. We have shown that human umbilical mesenchymal stem cells (HUMSCs) in Wharton's jelly possess stem cell properties. We previously demonstrated that HUMSCs could be induced to differentiate into neurons. When cultured in neuronal conditioned medium (NCM), human umbilical mesenchymal cells started to express neuron-specific proteins such as NeuN and neurofilament (NF), functional mRNAs responsible for the syntheses of subunits of the kainate receptor and glutamate decarboxylase and generating an inward current in response to evocation by glutamate.
At first, DcR3 treatment is in order to inhibit the inflammation. DcR3 is one of TNF family, and bind to FasL、Light、and TL1A. Previous studies report that DcR3 could reduce cell apoptosis in secondary injury by binding to FasL and decrease activated immune cells via reverse signal.
Besides inhibition immune response, we transplant the human umbilical mecenchymal stem cell to provide a regeneration environment. The human umbilical mecenchymal stem cell is the kind of get up easily and unrelated to process and rapid expansion in culture. The stem cell can be long-term survival in host and that has few immune response. So the human umbilical mensenchymal stem cell is very suitable for applying to transplantation.
In this study, we tested the potential of DcR3combined with human umbilical mesenchymal stem cell transplantation into ischemic brain of rat. Focal cerebral ischemia was induced by middle cerebral artery occlusion and reperfusion (MCAO). In our preliminary data, the changes of cerebral blood flow in the process of surgery and the ranges of damage areas of infracted brains were measured. There days after MCAO, DcR3 or DcR3 combined with HUMSCs were injection into the ischemic brain. These reduce immunoreaction and transplanted HUMSCs survived in the rat ischemic brain and significantly decreased the infracted brain area. Using magnetic resonance imaging (MRI), we observed that both DcR3 and DcR3 combined with HUMSCs injection prevented infracted cortex from atrophy. Furthermore, the recovery of behavioral deficits was significant, and neuronal metabolic activity improved after transplantation.
In conclusion, the combing DcR3 treatment and human umbilical mesenchymal stem cell transplantation may provide a new approach to restore stroke disease.
中文摘要 01
英文摘要 05
第一章 緒論 07
1.1 腦血管的分佈解剖學 07
1.2 腦中風的分類 08
1.3 腦中風的損傷機制 09
1.4 腦中風的預防與治療 13
1.5 以大白鼠大腦中動脈缺血再回流模式,
來模擬人類缺血性腦中風 14
1.6 中風後的神經新生作用 15
1.7 幹細胞移植修復腦中風之基礎研究 16
1.7.1 胚胎幹細胞 17
1.7.2 神經幹細胞 18
1.7.3 骨髓幹細胞 19
1.7.4 臍帶血幹細胞 20
1.8 人類臍帶間質幹細胞 21
1.9 Decoy Receptor 3 (DcR3) 的基礎研究 22
第二章 實驗目的 25
第三章 材料與方法 26
3.1 人類臍帶間質幹細胞之培養 26
3.2初級大腦皮質神經細胞之培養 26
3.3 實驗動物 27
3.4 腦缺血與再回流手術-大腦中動脈結紮與再回流
(Middle Cerebral Artery Occlusion;簡稱 MCAO) 28
3.5 實驗分組 28
3.6 人類臍帶間質幹細胞移植 29
3.7 DcR3 給予 30
3.8 大腦梗塞體積的測量 30
3.9 運動行為測試 31
3.10 核磁共振攝影
(Magnetic Resonance Imaging,簡稱 MRI) 31
3.11 正電子放射電腦斷層掃瞄攝影
(Positron Emission Tomography,簡稱 PET) 32
3.12 腦內微血管的變化 33
3.13 實驗動物犧牲、灌流固定、與冷凍切片 34
3.14 腦組織切片選取 34
3.15 結晶紫染色 35
3.16 組織免疫染色 35
3.17 統計分析 37
第四章 結果 38
4.1 DcR3不會造成體外培養的大腦皮質神經細胞受損 38
4.2 大腦中動脈結紮造成腦中風模式的成功建立 38
4.3 移植人類臍帶間質幹細胞並合併使用 DcR3,減少中風
大白鼠的梗塞大腦皮質範圍 38
4.3.1 以 TTC 染色發現,移植人類臍帶間質幹細胞結合
使用DcR3降低大腦受損區域 39
4.3.2 以 MRI 造影顯示,移植人類臍帶間質幹細胞合
併給予DcR3,可減少大腦梗塞區域 39
4.3.3 由腦巨觀顯示,移植人類臍帶間質幹細胞合併給予
DcR3,減少中風大白鼠的大腦皮質萎縮 42
4.3.4 以結晶紫染色發現,移植人類臍帶間質幹細胞合併
給予DcR3,避免中風大白鼠的大腦皮質萎縮 42
4.4 移植人類臍帶間質幹細胞合併使用 DcR3,梗塞大腦皮質內,
保留下來的神經細胞數目較多 43
4.5 移植人類臍帶間質幹細胞合併使用 DcR3,減緩急性期內
梗塞大腦皮質的發炎反應 44
4.6 以正子斷層造影發現,移植人類臍帶間質幹細胞合併使用 DcR3,可增進腦中風大白鼠大腦梗塞皮質內神經細胞的活性 45
4.7 移植人類臍帶間質幹細胞合併使用 DcR3,有助於損傷
大腦皮質處血管的新生或保留 47
4.8 移植人類臍帶間質幹細胞合併使用 DcR3,改善大白鼠中風
後之運動行為 48
4.9 人類臍帶間質幹細胞存活並分佈於大白鼠梗塞大腦皮質內 50
第五章 討論 51
5.1 DcR3 對於神經膠細胞的影響 51
5.2 移植人類臍帶間質幹細胞並合併給予 DcR3 可有效
減輕中風大白鼠的損傷 52
5.3 結論 55
第六章 參考文獻 56
第七章 圖表 68
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