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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉宏輝(Horng-Huei Liou) | |
| dc.contributor.author | Hsing-Yu Lin | en |
| dc.contributor.author | 林杏諭 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:11:10Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-06 | |
| dc.identifier.citation | Identification and Characterization of Neural Progenitor Cells in the Adult Mammalian Brain Series: Advances in Anatomy, Embryology and Cell Biology, Vol. 203
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17406 | - |
| dc.description.abstract | 背景：神經幹細胞(NSC)是一種具備新生與分化能力的細胞，可以進行細胞再生甚至組織再造，所以神經幹細胞的生長與分化是神經新生的重要關鍵，因此常被視為細胞治療的重要來源。近年來發現許多腦部發炎性疾病中，體內Stromal derived factor-1 (SDF-1)會被大量增加，並且同時出現大量神經幹細胞的新生與遷移。因此SDF-1極為可能是神經新生驅動活化的重要因子。
目標: 探討SDF- 1對小鼠神經幹細胞之特性維持與生長分化能力的影響以及其相關機轉的研究 研究方法：本篇論文利用體外培養小鼠初代神經幹細胞球，使用CXCR4拮抗劑, AMD3100競爭阻斷SDF-1活化神經幹細胞中CXCR4的訊息路徑。並且藉由分析形成之神經幹細胞球數量大小、形態特徵及細胞特性來評估缺少SDF-1作用時對於神經幹細胞球所造成之影響 結果：我們成功的從小鼠大腦組織培養出神經幹細胞並且藉由給予AMD3100阻斷神經幹細胞中SDF-1/CXCR4的訊息傳遞。研究結果發現AMD3100不會造成細胞死亡也不會影響神經幹細胞球之形成比率。但是AMD3100會顯著降低神經幹細胞球之平均大小，而且與劑量呈現正相關(控制組為1818.07±84.9 pixel2；AMD3100 0.1μg/ml為1411.01±107.7 pixel2；AMD3100 0.5μg/ml為906.20±97.8 pixel2；AMD3100 1.0μg/ml為626.60±66.3 pixel2)。同時也發現AMD3100會明顯減少神經幹細胞球中表現Ki67之細胞比例(控制組為52.25±8.45%；而AMD3100 1.0μg/ml為32.67±3.82%)，表示當神經幹細胞之CXCR4訊息路徑受阻斷時可能會因此抑制其增殖能力。此外，從流式細胞分析結果顯示AMD3100阻斷CXCR4後會降低神經幹細胞球中表現nestin之神經幹細胞比例(控制組為96.87±0.7%；AMD3100 1.0 μg/ml為90.6±2.6%)，但是會增加表現β III tubulin之神經細胞比例(控制組為52±1.4%；AMD3100 1.0 μg/ml為67.7±5.1%)，表示CXCR4訊息路徑的阻斷可能會因此導致神經幹細胞趨向神經分化而降低神經幹細胞之特性。西方墨漬法結果發現受到AMD3100作用後的神經幹細胞球，其REST和Notch的表現量明顯減低，表示神經幹細胞特性可能發生變化且趨向神經分化。同時也發現神經幹細胞球之pAkt和pS6蛋白表現量有顯著增加，因此推測Akt-mTOR訊息路徑可能是AMD3100影響神經幹細胞之增殖與分化活性的可能路徑。此外，增殖時期受AMD3100影響過之神經幹細胞球在誘發分化後，其分化神經的軸突長度較長(控制組為153.21±88.3μm；AMD3100 1.0 μg/ml 385.93±47.6 μm)和分支程度也會增加(控制組為1.08±0.12級；AMD3100 1.0 μg/ml為2.12±0.17級)，表示AMD3100可能潛在具備促進新生神經成熟的作用。另一方面，也發現神經幹細胞在增殖時期缺少SDF-1作用不僅會改變細胞增殖活性，也可能因此影響神經幹細胞球最終分化細胞之蛋白表現。 結論：本篇論文結果發現，當SDF-1/CXCR4訊息功能受到AMD3100的阻斷時，神經幹細胞之特性會降低並且促使神經幹細胞趨向神經分化，而這其中Akt-mTOR之訊息傳遞路徑可能參與其中。這代表SDF-1/CXCR4訊息路徑對神經幹細胞之特性維持可能扮演著十分重要的角色，也可能成為未來誘導神經幹細胞特性的重要標的。 | zh_TW |
| dc.description.abstract | Background：Neural stem cell (NSC) is a kind of cell has the ability for self-renewal and differentiation. Due to NSC is able to generate new-born cells and repopulate tissues, so the growth and development of NSC is the key of the neurogenesis. Thus, NSCs have been considered as an attractive source of cell-based therapy. Recently, it’s been reported that neuronal generation and migration occurred with a burst of SDF-1 elevation. Therefore, SDF-1 probably is the main regulator of driving neurogenesis.
Aim : To study the effects of SDF-1on NSC maintenance and its develo[1]ping ability and to further investigate their related mechanisms Methods : In this thesis, using CXCR4 antagonist, AMD3100 blocked the activation of CXCR4 signaling pathway by SDF-1 in the mice primary neurosphere culture. We analyzed the size and population of neurospheres, cell morphologic features, and cell expression markers to investigate the effects on neurospheres without SDF-1. Results : We successfully cultured primary neural stem cells to form neurospheres from postnatal mice brain and blocked the SDF-1/CXCR4 signaling pathway by AMD3100. We found that CXCR4 blockage by AMD3100 had no effects on the cell death and the neurosphere formation. However, AMD3100 significantly reduced the mean size of neurospheres, and it’s in a dose-dependent manner. (Control:1818.07±84.9 pixel2, AMD3100 0.1μg/ml : 1411.01±107.7 pixel2, AMD3100 0.5μg/ml : 906.20±97.8 pixel2, AMD3100 1.0μg/ml : 626.60±66.3 pixel2). We also found that AMD3100 decreased the expression percentage of Ki67-positive cells (Control:52.25±8.45%, AMD3100 1.0μg/ml: 32.67±3.82%). It indicated that CXCR4 signaling blockage inhibited NSC proliferation. Moreover, the results from flow cytometry analysis showed that blocking CXCR4 signaling in NSCs by AMD3100 decreased the percentage of nestin-positive cells (Control : 96.87±0.7%, AMD3100 1.0 μg/ml : 90.6±2.6%); nevertheless, increased the percentage of β III tubulin-positive cells (Control : 52±1.4%, AMD3100 1.0 μg/ml : 67.7±5.1%). It suggested that CXCR4 signaling blockage might promote NSC differentiation and result in the reduction of NSC property. Western blot showed that both REST and Notch expression level were decreased in AMD3100-treated neurosphere, and it represented the character of NSCs were probably changed and prompted to neuronal differentiation. Meanwhile, the pAkt and pS6 activity were significantly elevated, and it’s suggested that the induction of neuronal differentiation by AMD3100 was possibly through Akt-mTOR signaling activation. Besides, after induced neurosphere differentiation, the neurites length and branching level of those differentiated neurons from AMD3100 treatment may significantly increase (Control : 153.21±88.3μm, AMD3100 1.0 μg/ml : 385.93±47.6 μm) (Control : 1.08±0.12 level, AMD3100 1.0 μg/ml : 2.12±0.17 level). It indicated that AMD3100 have a potential ability to promote NSC maturation. On the other hand, loss of SDF-1 function at the proliferation stage of NSC might reduce NSCs proliferation abilities, and ultimately decreased the protein levels of differentiated neurons after induced differentiation. Conclusions : Our results showed that AMD3100 once blocking the SDF-1/CXCR4 signaling pathway, Akt-mTOR signaling pathway might involve in the decrease of NSC property and the increase in NSC differentiation. It indicated that SDF-1/CXCR4 signaling is quite important for NSC maintenance, and it could be a great target for induced NSCs in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:11:10Z (GMT). No. of bitstreams: 1 ntu-102-R00443005-1.pdf: 3281616 bytes, checksum: f2efa08f81fe8f5eb2a0fb0c6da452f0 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 摘要 i
Abstract iii 圖目錄 viii 表目錄 x 縮寫表 xi 第一章 緒論(Introduction) 1 第一節 神經新生 1 第二節 神經新生與細胞治療契機 1 第三節 神經幹細胞與神經新生 2 第四節 神經幹細胞和前驅細胞與神經幹細胞球 3 第五節 SDF-1/CXCR4路徑與神經新生 5 第六節 SDF-1/CXCR4之訊息路徑 7 第七節 CXCR4之專一性拮抗劑：AMD3100 (plerixafor) 8 第八節 NSC和NPC中CXCL12-CXCR4之調控角色 8 第九節 研究動機與目的 9 第二章 實驗材料與方法(Materials and Methods) 11 第一節 實驗動物 11 第二節 實驗藥品 11 第三節 細胞培養 11 第四節 神經細胞球形成能力分析 (Neurosphere formation assay) 13 第五節 免疫細胞化學染色法（Immunocytochemistry） 14 第六節 反轉錄酶-聚合酶連鎖反應(reverse transcriptase polymerase chain reaction; RT-PCR) 15 第七節 細胞存活率分析 (WST -8 Assay) 16 第八節 LDH釋放量之測定 (LDH Assay) 17 第九節 西方墨漬法 (Western Blot) 18 第十節 流式細胞儀分析 (Flow cytometry analysis) 21 第十一節 神經軸突結構測量(Morphometric measurements on neurites) 21 第十二節 統計分析 (Statistic analysis) 22 第三章 結果(Results) 23 第一節 體外培養初代神經幹細胞模式 23 第二節 增殖環境下，SDF-1/CXCR4訊息路徑對神經幹細胞生長之影響 25 第三節 SDF-1/CXCR4訊息阻斷會潛在影響神經幹細胞球之特性組成之可能機轉 32 第四節 SDF-1/CXCR4訊息功能抑制可能會促進分化神經細胞之成熟 33 第五節 AMD3100早期阻斷神經幹細胞SDF-1/CXCR4訊息路徑最終可能會造成分化神經的喪失 34 第四章 討論(Discussion) 36 第一節 總述 36 第二節 SDF-1/CXCR4訊息路徑於神經幹細胞增殖與分化能力之角色 36 第三節 SDF-1/CXCR4訊息路徑調控神經幹細胞增殖與分化發展之機轉 38 第四節 SDF-1/CXCR4訊息路徑對細胞分化和遷移之影響 39 第五節 檢討與未來展望 40 參考文獻(References) 76 | |
| dc.language.iso | zh-TW | |
| dc.title | SDF-1調控神經幹細胞之生長及分化機轉之研究 | zh_TW |
| dc.title | Studies on the mechanisms of SDF-1-regulated neural stem cell proliferation and differentiation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 林泰元(Thai-Yen Ling) | |
| dc.contributor.oralexamcommittee | 符文美,郭紘志 | |
| dc.subject.keyword | 神經幹細胞,神經新生,SDF-1(Stromal derived factor-1),神經幹細胞球,CXCR4拮抗劑,Akt-mTOR, | zh_TW |
| dc.subject.keyword | NSC,neurogenesis,SDF-1(Stromal derived factor-1),neurosphere,CXCR4 antagonist,Akt-mTOR signaling pathway, | en |
| dc.relation.page | 82 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-08-06 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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