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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84177完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐莞曾(Wan-Tseng Hsu) | |
| dc.contributor.author | Yueh-Chen Chen | en |
| dc.contributor.author | 陳玥蓁 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:05:50Z | - |
| dc.date.copyright | 2022-10-20 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-09-27 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84177 | - |
| dc.description.abstract | 研究背景與目的 冠狀動脈阻塞導致缺氧的心肌短時間內大量死亡，稱為心肌梗塞 (myocardial infarction)，當前臨床處置主要為經皮冠狀動脈介入術，然而缺血再灌注傷害，致使部分病人預後不佳，可能併發心臟衰竭。 脂肪幹細胞 (adipose-derived stem cell, ASC) 可透過旁分泌生物活性因子，調控梗塞處的心肌發炎反應並進行再生修復，具有縮減缺血再灌注氧化壓力及救援瀕死的心肌細胞之潛能。然而，心肌梗塞病人多半有代謝症候群的共病，自體ASC功能減損，因此需發展強化ASC的方法，並應用其條件培養基 (conditioned media, CM) 於心肌保護。 研究方法與結果 本研究第一部份以心肌細胞建立模擬缺血再灌注 (simulated ischemia reperfusion, SIR) 的療效測試平台，分析收集自代謝症候群疾病模式小鼠Tsumura, Suzuki, obese diabetes (TSOD) 的ASC-CM之心肌保護效果，結果指出ASCTSOD-CM有效回復HL-1心肌細胞的代謝活性 (48% vs 33%, p < 0.05)，卻會加劇心肌細胞總體凋亡 (2.53倍 vs 1.86倍, p < 0.05)。因此，第二部分研究進一步發展強化ASC心肌保護潛能的方法開發，分別以6種化合物合併雙重細胞激素預處理收集多種ASC-CM，稱為優化CM，經由定性與定量分析所含的滋養因子，篩選候選CM，未經預處理的CM則稱為基礎CM (ASCBALB/c-CTL CM)。功能性測試結果指出基礎CM及優化CM均能有效回復損傷心肌細胞之代謝活性 (CTL CM = 63%, BA 750 CM = 59%, SAHA 0.5 CM = 55%, p < 0.05)，減少再灌注時細胞初期和總體凋亡比例 (SIR = 3.2 倍, CTL CM = 1.93 倍, BA 750 CM = 1.85 倍, SAHA 0.5 CM = 2.18 倍, p < 0.05)。進一步我們利用mtSOX螢光染劑標定粒線體的超氧化物，以高通量影像系統所偵測的螢光強度定量超氧化物的生成量，結果顯示特定組別之條件培養基可降低粒線體超氧化物的生成 (SIR = 24393, CTL CM = 23438, SAHA 0.5 CM = 23463, p < 0.05)。 結論 本研究以ASCTSOD-CM療效分析結果推導出具代謝症候群共病之病人自體ASC的治療潛能不佳，因此開發ASC策略，優化CM於模擬缺血再灌注時可有效救援心肌細胞，然而，基礎CM與優化CM療效並無顯著差異。本研究可作為應用及優化ASC條件培養基於開發幹細胞治療產品之參考，而未來應將發展重心放在提高CM的濃度與療效穩定性，並可深入探討預處理策略調控ASC功能的機轉，提升促存活因子之分泌。 | zh_TW |
| dc.description.abstract | Background and Research Aim The blockage of the coronary arteries leads to the massive death of the ischemia myocardium in a short period called myocardial infarction (MI). The dominant treatment, percutaneous coronary intervention, can temporarily treat MI. However, ischemia and reperfusion injury results in a poor prognosis among some patients, which may contribute to complicated heart failure. Adipose-derived stem cells (ASCs) and their paracrine factors simultaneously modulate the inflammatory responses and repair the infarcted area. ASCs may exert their potential when reducing oxidative stress induced by a reperfused blood flow to salvage dying cardiomyocytes. Patients with MI often have comorbidities such as metabolic syndrome or other cardiovascular disorders, which are responsible for insufficient ASCs. Consequently, researchers must devise methods to optimize autologous ASC function and use ASC-conditioned media (CM) for cardioprotection. Methods and Results In the first part of our study, we developed a simulated ischemia-reperfusion (SIR) platform. We analyzed the cardioprotective effect of ASC-CM derived from Tsumura, Suzuki, obese diabetes (TSOD) mice in vitro. We named ASC-CM derived from TSOD mice ASCTSOD-CM. The ASCTSOD-CM could significantly restore the metabolic activity of HL-1 cardiomyocytes (48% vs 33%, p < 0.05), but exacerbated the total apoptosis (2.53 vs 1.86, p < 0.05). Therefore, in the second part of the study, we demonstrated that the ASCBALB/c could protect human umbilical vein endothelial cells from high-intensity oxidative injury. To further enhance the cardioprotective function of ASCs, we primed the ASCs with dual cytokines and six compounds through high throughput screening. The optimized CM was selected after qualitative and quantitative analyses of trophic factors. We called the ASC-CM derived from BALB/c mice without priming ASCBALB/c-CTL CM, abbreviated CTL CM. The CTL CM and priming CM could significantly restore the metabolic activity of injured cardiomyocytes (CTL CM = 63%, BA 750 CM = 59%, SAHA 0.5 CM = 55%, p < 0.05). Moreover, the application of CM attenuated the excessive apoptosis caused by ischemia and reperfusion injury (SIR = 3.2, CTL CM = 1.93, BA 750 CM = 1.85, SAHA 0.5 CM = 2.18, p < 0.05). After labeling the mitochondrial superoxide with mtSOX dye, we detected and quantified the mtSOX fluorescence using a high-content imaging system. The result indicated that the specific groups of CM significantly reduced the generation of mitochondrial superoxide (SIR = 24393, CTL CM = 23438, SAHA 0.5 CM = 23463, p < 0.05). Conclusion ASCs from MI donors complicated with metabolic syndrome have limited utility; thus, we developed an ASC priming strategy. The optimized CM efficiently rescued the damaged cardiomyocytes; however, the priming CM was not superior to the original CMs. Moreover, our findings could be applied to develop novel ASC-based products. Future research should improve the concentration and effectiveness of ASC-CM, and explore the mechanism underlying the effects of pro-survival factors. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T22:05:50Z (GMT). No. of bitstreams: 1 U0001-2609202211310000.pdf: 36345074 bytes, checksum: eea5f909f6443bdb7bcacc004a592ed2 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract v 圖目錄 x 表目錄 xi 第一章 緒論 1 壹、 幹細胞簡介 1 一、 幹細胞簡介 1 二、 脂肪幹細胞 (adipose-derived stem cell, ASC) 概論 2 （一） 間葉幹細胞 (mesenchymal stem cell, MSC) 起源與組織來源 2 （二） 脂肪組織取得間葉幹細胞之發展歷程 2 （三） 脂肪幹細胞的生物特性 3 三、 間葉幹細胞的旁分泌作用及潛能 4 （一） MSC的旁分泌修復機制 4 （二） 具備心肌保護潛能之因子：amphiregulin、HGF、EGF、VEGF、PLGF、IL-6和MCP-1 5 四、 發展及應用MSC於治療心肌梗塞之策略 6 五、 MSC臨床治療困境與優化方案 8 （一） 目前MSC之臨床治療與困境 8 （二） 發展MSC條件培養基 (conditioned media, CM) 的優勢 9 （三） 強化MSC的治療潛能 — 預處理 (priming) 概念之興起 9 （四） 體外模式預處理概念 9 （五） 其他體內模式預處理策略 10 六、 發展新穎優化ASC功能之體外模式策略 10 貳、 心肌梗塞簡介 13 一、 心肌梗塞之病理變化 13 （一） 心肌細胞死亡 13 （二） 氧化壓力 15 （三） 粒線體的影響與應對機制 16 （四） 免疫發炎反應 16 （五） 心臟代償機制 17 二、 心肌梗塞之體外模式平台先導性研究 18 參、 當前研究限制 20 肆、 研究目的 20 第二章 研究方法 21 壹、 研究設計與架構 21 貳、 分析代謝症候群模式ASCTSOD-CM之體外心肌保護效果 22 一、 代謝症候群疾病模式小鼠ASCTSOD-CM培養基收集平台 22 二、 探討ASCTSOD-CM之體外心肌細胞保護效果 24 參、 優化ASCBALB/C心肌保護功能之方法開發 30 一、 ASCBALB/c的旁分泌細胞保護機制 30 二、 發展ASCBALB/c優化培養基之收集平台 32 三、 ASCBALB/c優化培養基之體外心肌保護效果 37 第三章 研究結果 40 壹、 分析代謝症候群疾病模式ASCTSOD-CM之體外心肌保護效果 40 一、 ASCTSOD-CM於回復再灌注損傷HL-1心肌細胞代謝活性之效果 40 二、 ASCTSOD-CM於再灌注損傷HL-1心肌細胞凋亡之影響 40 貳、 優化ASCBALB/C心肌保護功能之方法開發 41 一、 ASCBALB/c藉由旁分泌機制保護血管內皮細胞 41 二、 優化ASCBALB/c條件培養基收集平台的建立 42 （一） 建立雙重促發炎細胞激素與收集時長的預處理條件 42 （二） 建立候選化合物的預處理濃度條件 42 三、 分析優化ASCBALB/c條件培養基中心肌保護之富集因子 43 四、 ASCBALB/c優化培養基回復再灌注損傷HL-1心肌細胞代謝活性之效果 44 五、 ASCBALB/c優化培養基於再灌注損傷HL-1心肌細胞凋亡之影響 45 六、 ASCBALB/c優化培養基於心肌細胞粒線體抗氧化之能力 46 第四章 討論 47 壹、 應用代謝症候群疾病模式ASCTSOD-CM於心肌保護 47 一、 ASCTSOD-CM加劇心肌細胞凋亡的可能原因 47 二、 肥胖及代謝症候群之於ASC的影響與應用發展可能 47 貳、 優化ASCBALB/C心肌保護功能之方法開發 48 一、 ASCBALB/c優化培養基收集平台之可能機轉與發展 49 二、 模擬心肌缺血再灌注平台的研究限制 50 三、 ASCBALB/c優化培養基之劑型影響 53 參、 ASCBALB/C條件培養基應用注意事項 55 第五章 結論與展望 56 第六章 圖 57 第七章 表83 參考文獻 93 附錄 104 專有名詞之中英文暨縮寫對照表 104 | |
| dc.language.iso | zh-TW | |
| dc.subject | 組蛋白去乙醯酶抑制劑 | zh_TW |
| dc.subject | 心肌梗塞 | zh_TW |
| dc.subject | 缺血再灌注損傷 | zh_TW |
| dc.subject | 脂肪幹細胞 | zh_TW |
| dc.subject | 心肌保護 | zh_TW |
| dc.subject | 條件培養基 | zh_TW |
| dc.subject | 丁酸 | zh_TW |
| dc.subject | butyrate | en |
| dc.subject | HDAC inhibitor | en |
| dc.subject | myocardial infarction | en |
| dc.subject | reperfusion injury | en |
| dc.subject | adipose-derived stem cell | en |
| dc.subject | cardioprotection | en |
| dc.subject | conditioned media | en |
| dc.title | 應用與優化脂肪幹細胞條件培養基之心肌保護效果 | zh_TW |
| dc.title | Optimizing the Cardioprotective Potential of Conditioned Media Derived from Adipose-derived Stem Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳玉怜(Yuh-Lien Chen),郭薇雯(Wei-Wen Kuo),余兆武(Zhao-Wu Yu) | |
| dc.subject.keyword | 心肌梗塞,缺血再灌注損傷,脂肪幹細胞,心肌保護,條件培養基,丁酸,組蛋白去乙醯酶抑制劑, | zh_TW |
| dc.subject.keyword | myocardial infarction,reperfusion injury,adipose-derived stem cell,cardioprotection,conditioned media,butyrate,HDAC inhibitor, | en |
| dc.relation.page | 107 | |
| dc.identifier.doi | 10.6342/NTU202204057 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-09-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| dc.date.embargo-lift | 2027-09-26 | - |
| 顯示於系所單位： | 藥學系 | |
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