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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78196完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂仁(Jean Lu) | |
| dc.contributor.author | Wei-Ju Chen | en |
| dc.contributor.author | 陳薇如 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:45:32Z | - |
| dc.date.available | 2025-08-17 | |
| dc.date.copyright | 2020-09-16 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-17 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78196 | - |
| dc.description.abstract | 維持延展性富潛能幹細胞潛能的訊息傳遞機制與膽固醇在潛能幹細胞中的功能還不是被研究得很清楚。本次研究報導了抑制Podocalyxin-like protein 1 (PODXL) 表現會抑制富潛能幹細胞與延展性富潛能幹細胞自我更新的能力，進而造成c-MYC 與端粒酶的蛋白表現量下降，並且抑制逆編程誘導性富潛能幹細胞與逆編程延展性富潛能幹細胞的細胞聚落產生的數量。反之，若增強Podocalyxin-like protein 1 (PODXL) 表現，則會促進富潛能幹細胞與延展性富潛能幹細胞自我更新的能力，進而造成c-MYC 與端粒酶的蛋白表現量上升，並且增加逆編程誘導性富潛能幹細胞與逆編程延展性富潛能幹細胞的細胞聚落產生的數量。我們也發現PODXL 可以調控hydroxymethylglutaryl-CoA reductase (HMGCR) 與sterol regulatory element-binding proteins 1/2 (SREBP1/2) 的表現量去調控細胞內膽固醇的生合成。更重要地，富潛能幹細胞相對於成體幹細胞 (例如: 神經性成體幹細胞，骨間質幹細胞) 與已經分化的體細胞 (例如: 纖維母細胞)，對於膽固醇抑制劑處理後的反應更為敏感，結果造成自我更新能力下降。 然而，補充膽固醇可以彌補因為抑制PODXL表現，所造成的富潛能幹細胞自我更新能力的下降。我們更進一步地發現PODXL 可以透過調控脂筏(lipid rafts)的形成，並且透過控制F-actin骨架蛋白纖維形成與膽固醇合成，進而促進新生脂筏形成; 並調節脂筏性蛋白分子integrin α2 (ITGA2) 表現。抑制ITGA2 後的確也會抑制富潛能幹細胞自我更新能力的下降。總結，本研究揭露PODXL在富潛能幹細胞與延展性富潛能幹細胞中扮演了透過調控膽固醇細胞代謝維持自我更新能力的重要地位。 | zh_TW |
| dc.description.abstract | The signaling mechanisms of extended pluripotency and cholesterol in human pluripotent stem cells (hPSCs) have rarely been investigated. Here, we report that downregulation of Podocalyxin-like protein 1 (PODXL) in undifferentiated hPSCs significantly blocks self-renewal, leads to decreased protein expression of c-MYC and telomerase, and inhibits the formation of induced pluripotent stem cell (iPSC) and extended pluripotent stem cell (EPSC) colonies. Accordingly, overexpression of PODXL promotes hPSC self-renewal, c-MYC and telomerase expression, and iPSC/EPSC formation. PODXL also regulates hydroxymethylglutaryl-CoA reductase (HMGCR) and sterol regulatory element-binding proteins 1/2 (SREBP1/2) expression. Importantly, hPSCs are more sensitive to cholesterol depletion than neural stem cells, bone marrow stem cells and fibroblasts, resulting in pluripotency loss, whereas cholesterol can fully restore PODXL knockdown-mediated pluripotency loss. Moreover, PODXL regulates lipid raft formation possibly by serving as a nucleating factor to activate actin polymerization and coupled with cholesterol biosynthesis and transmits signals by controlling integrin α2 (ITGA2) in lipid rafts. Finally, loss of ITGA2 blocks hPSC renewal. Our data highlight the important roles of PODXL in controlling cholesterol metabolism to achieve hPSC self-renewal. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:45:32Z (GMT). No. of bitstreams: 1 U0001-1308202021513700.pdf: 6875258 bytes, checksum: 0e9f43e1f1fc35d2c8b1477bb90bb56a (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 口試委員審定書 ii 誌謝 iii 中文摘要 iv Abstract v List of Figures vi List of Tables vii Chapter 1. Introduction 1 1.1 Pluripotent stem cells (PSCs) and extended pluripotent stem cells (EPSCs) 1 1.2 Podocalyxin-like protein 1 (PODXL) 1 1.3 Metabolism in stem cell pluripotency 2 1.4 Interspecies chimera formation 3 Chapter 2. Materials and methods 3 Chapter 3. PODXL’s expression profile in human early embryos and pluripotent stem cells and non-pluripotent stem cells 24 Chapter 4. Manipulations of PODXL level to investigate the effects on self-renewal of human primed state PSCs and extended PSCs 28 Chapter 5. PODXL is important for induced pluripotent stem cell (iPSC) reprogramming 39 Chapter 6. Examination of off-target effects in loss of function experiments in hPSCs 42 Chapter 7. PODXL regulates de novo cholesterol biosynthesis pathway through SREBP1, SREBP2 and HMGCR 47 Chapter 8. PODXL activates SREBPs via RAC1/CDC42/actin network 54 Chapter 9. Cholesterol is pivotal for hPSC pluripotency and survival 58 9.1 hPSCs are hypersensitive to cholesterol inhibition than hNSC, hBMSCs and finroblasts 59 9.2 Cholesterol rescues the shPODXL phenotype 63 Chapter 10. PODXL can regulate lipid raft dynamics and activate integrin pathway. 66 Chapter 11. PODXL regulates lipid raft associated protein, ITGA2. 70 Chapter 12. PODXL may promotes extended potency of hEPSCs in a human/mouse interspecies chimeric embryo model 76 Conclusion and future perspectives 80 Reference 84 Appendix 91 | |
| dc.language.iso | en | |
| dc.subject | PODXL | zh_TW |
| dc.subject | 胚胎幹細胞 | zh_TW |
| dc.subject | 誘導性富潛能幹細胞 | zh_TW |
| dc.subject | 延展性富潛能幹細胞 | zh_TW |
| dc.subject | 膽固醇生合成 | zh_TW |
| dc.subject | 細胞逆編程序 | zh_TW |
| dc.subject | 脂筏 | zh_TW |
| dc.subject | integrin 訊息路徑 | zh_TW |
| dc.subject | induced pluripotent stem cells | en |
| dc.subject | PODXL | en |
| dc.subject | integrin signaling | en |
| dc.subject | lipid rafts | en |
| dc.subject | reprogramming | en |
| dc.subject | cholesterol biosynthesis | en |
| dc.subject | embryonic stem cells | en |
| dc.subject | extended pluripotent stem cells | en |
| dc.title | Podocalyxin-like Protein 1透過膽固醇生合成路徑促進人類富潛能幹細胞的自我更新能力 | zh_TW |
| dc.title | Podocalyxin-like Protein 1 Regulates Human Pluripotent Stem Cell Self-Renewal through the Cholesterol Biosynthesis Pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 吳漢忠(Han-Chung Wu),宋麗英(Li-Ying Sung),林劭品(Shau-Ping Lin),陳佑宗 (You-Tzung Che),蔡素宜(Su-Yi Tsai) | |
| dc.subject.keyword | PODXL,胚胎幹細胞,誘導性富潛能幹細胞,延展性富潛能幹細胞,膽固醇生合成,細胞逆編程序,脂筏,integrin 訊息路徑, | zh_TW |
| dc.subject.keyword | PODXL,embryonic stem cells,induced pluripotent stem cells,extended pluripotent stem cells,cholesterol biosynthesis,reprogramming,lipid rafts,integrin signaling, | en |
| dc.relation.page | 92 | |
| dc.identifier.doi | 10.6342/NTU202003331 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-18 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| dc.date.embargo-lift | 2025-08-17 | - |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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