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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 呂仁(Jean Lu),黃筱鈞(Hsiao-Chun Huang) | |
dc.contributor.author | Pei-Lun Lai | en |
dc.contributor.author | 賴培倫 | zh_TW |
dc.date.accessioned | 2021-06-16T09:28:07Z | - |
dc.date.available | 2022-07-20 | |
dc.date.copyright | 2017-07-20 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-04-26 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59564 | - |
dc.description.abstract | 人類間質幹細胞(MSCs)具有多功能分化特性(multipotency) 、免疫調節能力、並且無致瘤性(tumorigenesis) 。因此在臨床應用上安全性佳,於再生醫學和細胞治療極有應用價值。迄今,MSCs已經批准在臨床上治療移植物抗宿主病(GVHD),退行性關節炎(Arthritis)等疾病。目前大約有706個相關的臨床試驗對至少10種不同疾病進行測試。利用化學藥物配合生長因子轉化纖維母細胞成為特定具功能性的細胞可避免因為病毒感染或質粒轉染的插入誘變、病毒製備過程的繁瑣、以及轉染/轉導(transfection/transduction)技術上的麻煩。因此利用化學誘導方法改變細胞命運近來引發極大關注。過去並無研究報導能以化學藥物(chemicals)誘導人類皮膚纖維母細胞轉換為間質幹細胞(induced MSCs, iMSCs)。本研究首度發現利用藥物能在六天內將人類真皮之纖維母細胞(dermal fibroblasts)轉換為iMSCs,平均轉換率為38%。這些iMSCs與fibroblasts不同,與天然間質幹細胞一樣具有高度克隆性。此外,我們的微陣列分析顯示,iMSCs與其誘導來源之纖維母細胞相較,其分子特徵類似於骨髓間質幹細胞(BMMSCs)。 iMSCs滿足國際細胞治療學會(ISCT)對間質幹細胞定義的所有標準,可以進一步分化成成骨細胞,脂肪細胞和軟骨細胞,達到與BMMSCs相當的程度。且iMSC可以在常規培養基中(去除藥物狀態下)不失功能性繼代培養至少8代。在免疫調節方面,iMSCs如BMMSCs一樣能有效抑制內毒素(LPS)所誘導小鼠之急性肺損傷,可以降低肺損傷指數與致死率。另外我們發現3種藥(SB202190, SP600125, Go6983)對於產生iMSCs是不可少的,而6種藥(SP600125, SB202190, Go6983, Y-27632, PD0325901, CHIR99021)之產率最佳。總體而言,本研究揭示了一個全新的策略,誘導皮膚纖維母細胞轉換為iMSCs,於細胞生物學和再生醫學的發展與應用有極大助益。 | zh_TW |
dc.description.abstract | Due to the multipotency, immune-modularity, and the safety concern without tumorigenicity, human mesenchymal stromal/stem cells (MSCs) hold great promise in regenerative medicine and cell therapies. To date, MSCs already approved to treat Graft-versus-host disease, and degenerative arthritis in human and undergoing 706 clinical trials for the treatment of at least 10 different kinds of disease. To avoid (1) insertional mutagenesis by virus infection or plasmid transfection, (2) the tedious processes of virus preparation, and (3) repeated transfection/transduction, the use of chemical/growth factors to convert fibroblasts to functional cells has drawn substantial attention recently. However, no previous study has generated induced MSC (iMSCs) from skin fibroblasts with chemicals and/or growth factors. Herein, we established the first method to generate functional iMSCs from primary human dermal fibroblasts by solely small molecules with or without growth factors. The protocol can enrich iMSCs in only 6 days with an average conversion rate of 38%. Like traditional stem cells, only iMSCs, but not fibroblasts have clonogenicity. In addition, our microarray data displayed that iMSCs generated from one neonatal and two adult fibroblasts are more similar to bone marrow MSCs (BMMSCs) while compared to their parental fibroblasts. The phenotype of iMSCs fulfills all of the criteria of traditional MSCs as determined by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT). Most of all, the iMSCs can be further differentiated into osteoblasts, adipocytes, and chondrocytes to a degree comparable to BMMSCs. The chemicals can be removed, and iMSCs can expand in regular culture medium up to 8 passages. Of note, the iMSCs can suppress endotoxin (lipopolysaccharide, LPS)-mediated acute lung injury as effectively as BMMSCs by completely recuse the lethality and decrease injury score. We found 3 chemicals (SB202190, SP600125, Go6983) were essential for producing iMSCs while 6 chemicals (SP600125, SB202190, Go6983, Y-27632, PD0325901, CHIR99021) gave the best efficiency. Overall, in this study, we reveal a brand new strategy and breakthrough protocol to generate iMSCs from skin fibroblasts that mimic BMMSCs. Thus, iMSCs can be an easily accessible resource to enrich sufficient BMMSC like cells for research in cell biology and regenerative medicine. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T09:28:07Z (GMT). No. of bitstreams: 1 ntu-106-D01b48001-1.pdf: 4738125 bytes, checksum: 6df3e1650e471a770f50bb2ff68f3569 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝 i
中文摘要 iii Abstract v Table of Contents vii List of Figures ix 1. Introduction 1 1-1. Background and significance 1 1-2.Chemical Modulation in Cell Reprogramming 4 1-3. Mesenchymal Stem Cells and the clinical application 11 1-4. MSCs in the treatment of acute lung injury (ALI) 13 1-5. Hypothesis and Specific aims 16 2. Materials and methods 18 2-1. Reagents 18 2-2. Cell culture 18 2-3. Generation of iMSCs 19 2-4. Flow cytometry and cell sorting 20 2-5. CFU-F negative linear relationship assay 20 2-6. Microarray analysis 21 2-7. Osteogenic differentiation 21 2-8. Alkaline phosphatase activity assay 22 2-9. Alizarin Red S staining 22 2-10. Adipogenic differentiation 23 2-11. Oil Red O staining 23 2-12. Chondrogenic differentiation 23 2-13. Alcian blue staining 24 2-14. Endotoxin-induced acute lung injury in mice 24 2-15. Multiplex bead array assay 27 2-16. Colony forming unit-fibroblast (CFU-F) assay 27 2-17. Immunofluorescence assay 28 2-18. Lentivirus production and cells infection 28 2-19.Immunofluorescence analysis of lung 29 2-20. Statistical analysis 30 3. Results 31 3-1. Generation of MSC-like cells from human dermal neonatal fibroblasts using a chemical and growth factor cocktail 31 3-2. iMSCs have similar molecular signatures to BMMSCs 32 3-3. The conversion of fibroblasts into SSEA-4highPODXLhigh cells is reproducible 33 3-4. iMSCs express all traditional MSC markers 34 3-5. iMSCs are multipotent cells similar to BMMSCs 35 3-6. iMSCs, like BMMSCs, markedly decrease the fatality of endotoxin-induced acute lung injury in a mouse model and demonstrate anti-inflammation ability 36 3-7. Three to six chemicals are sufficient to generate iMSCs 38 4. Discussion 40 5. Conclusion 48 6. Reference 49 7. Appendix 115 List of Table TABLE 1. COMPOSITION OF THE CHEMICAL COCKTAIL (6C+3GF) FOR IMSC GENERATION 84 TABLE 2. CHEMICAL COMPOUNDS TESTED FOR INDUCING IMSCS FROM FIBROBLASTS. 85 TABLE 3. 418 PROBES FOR PRINCIPLE COMPONENT ANAYLSIS (PCA) 90 List of Figures FIGURE 1. SCHEMATIC DIAGRAM AND DERIVATION OF IMSCS 61 FIGURE 2. GENERATION OF SSEAHIGH PODXLHIGHCELLS AFTER THE TREATMENT WITH SIX CHEMICAL AND THREE GROWTH FACTORS. 62 FIGURE 3. FLOW CYTOMETRY ANALYSIS OF OCT4 PROTEIN EXPRESSION IN HUMAN FIBROBLASTS, IMSCS, BMMSCS, AND HUMAN EMBRYONIC STEM CELLS (HESCS). 63 FIGURE 4. THE PRINCIPAL COMPONENT ANALYSIS OF THE EXPRESSION OF STEMNESS GENES IN THREE DIFFERENT DERMAL FIBROBLASTS (CRL2097, DF440547, AND DF443480). 64 FIGURE 5. ENRICHMENT OF GENE ONTOLOGY (GO) BIOLOGICAL PROCESSES IN IMSCS. 66 FIGURE 6. THE CHEMICAL COCKTAIL (6C+3GF) REPRODUCIBLY CONVERTED HUMAN PRIMARY FIBROBLASTS INTO IMSCS WITH HIGH EFFICIENCY. 67 FIGURE 7. SSEA-4 AND PODXL ABUNDANTLY EXPRESSED IN IMSCS CULTURED FOR 8 PASSAGES. 68 FIGURE 8. ONLY SSEA-4HIGHPODXLHIGH CELLS CAN DIFFERENTIATE INTO OSTEOCYTES AND ADIPOCYTES. 69 FIGURE 9. THE EXPRESSION LEVELS OF MSC MARKERS IN IMSCS. 70 FIGURE10. IMSCS DERIVED FROM NEONATAL DERMAL FIBROBLASTS CRL2097 ARE MULTIPOTENT AND CAN DIFFERENTIATE INTO OSTEOBLASTS, ADIPOCYTES, AND CHONDROCYTES. 71 FIGURE 11. THE MULTIPOTENCY OF IMSCS INDUCED FROM ADULT FIBROBLASTS. 73 FIGURE 12. IMSCS, LIKE BMMSCS, MARKEDLY DECREASE THE FATALITY OF ENDOTOXIN-INDUCED ACUTE LUNG INJURY IN A MOUSE MODEL AND DEMONSTRATE ANTI-INFLAMMATION ABILITY. 75 FIGURE 13. LOW LEVELS OF PROINFLAMMATORY CYTOKINES DETECTED IN THE LPS-INDUCED LUNG INJURY MICE INJECTED WITH IMSCS/BMMSCS. 77 FIGURE 14. IMSCS AND BMMSCS DID NOT CONTRIBUTE TOMOUSE ALVEOLAR TISSUES OR MIGRATE TO BONE MARROW WITHIN 48-HOUR PERIOD. 78 FIGURE 15. CYTOKINES ARE DISPENSABLE FOR THE CONVERSION OF HUMAN FIBROBLASTS INTO IMSCS. 80 FIGURE 16. THE EVALUATION OF THE EFFICACY OF IMSC GENERATION AND THE OPTIMIZATION OF THE COCKTAIL COMPOSITIONS. 81 FIGURE 17. THE GRAPHICAL ABSTRACT OF CHEMICALLY INDUCED HUMAN MSCS FROM FIBROBLASTS. 83 | |
dc.language.iso | en | |
dc.title | 利用藥物高效率轉換人類皮膚纖維母細胞為誘導式間質幹細胞 | zh_TW |
dc.title | Efficient Generation of Chemically Induced Mesenchymal Stem Cells from Human Dermal Fibroblasts | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林劭品(Shau-Ping Lin),陳佑宗(You-Tzung Chen),蔡素宜(Su-Yi Tsai) | |
dc.subject.keyword | 間質幹細胞,化學藥物,細胞轉換,重編程,免疫調節,急性肺損傷,再生醫學,細胞治療, | zh_TW |
dc.subject.keyword | multipotent,mesenchymal stromal/stem cells,fibroblasts,chemicals,small molecules,conversion,acute lung injury,cell therapy,regenerative medicine, | en |
dc.relation.page | 116 | |
dc.identifier.doi | 10.6342/NTU201700777 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-04-28 | |
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 |
顯示於系所單位: | 基因體與系統生物學學位學程 |
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