臺灣博碩士論文加值系統

細胞之細胞週期會影響體細胞核轉置（SCNT）之效率，進而影響細胞再程式化之效率，另外，有研究報告指出非洲爪蟾蛋萃取物（Xenopus laevis egg extracts, XEE）處理後之細胞（extract treated cells, ETCs）可進行再程式化，使細胞重新表現分化多能性基因，如oct4、sox2與nanog。因此，本論文之研究目的為探討停留於不同細胞週期之小鼠體細胞，經XEE處理後，其再程式化形成分化多能性（pluripotent cells）與類胚胎生殖（embryonic germ, EG）細胞之影響。試驗一， 小鼠NIH/3T3細胞株與MEFs（mouse embryonic fibroblasts）以0.2 % 或0.5 % BS（bovine serum）培養3或5天，均可顯著使細胞停留於G0/G1期；而NIH/3T3s以0.5、1.0或1.5 μg/ml秋水仙素（colchicine）處理1天，MEFs則是處理2天可使細胞顯著停留於G2/M期，而達到細胞週期一致化結果。試驗二，選擇0.5 % BS培養3天或0.5 μg/ml秋水仙素處理1天之NIH/3T3s以爪蟾蛋萃取物處理，發現NIH/3T3s於萃取物處理後第7與8天所有組別之腫瘤抑制因子（p53、p21及p16）、多能性markers（Oct4、Sox2及Nanog）與始基生殖細胞（primordial germ cells, PGCs）markers（Blimp1及Stella）表現量不高且不穩定，在第9天時，秋水仙素處理組形態變成圓球狀形態之細胞較多，也發現腫瘤抑制因子、多能性markers及PGC markers表現量相對增加，且以免疫細胞化學染色（immunocytochemical, ICC）分析，發現其具有Oct4與Nanog表現；以0.2 % BS培養5天或0.5 μg/ml秋水仙素處理1天之MEFs於萃取物處理後第7-9天，雖然所有處理組皆可表現多能性markers，但腫瘤抑制因子、多能性與PGC markers表現不穩定。試驗三，NIH/3T3s經萃取物處理後培養至第7或8天後，再移至PGCM中培養24 h，於第7天換PGCM者，發現colchicine之Blimp1、Stella及Sox2之表現顯著較高，而第8天更換者，則是血清飢餓（serum starvation）之Blimp1之表現顯著較高，進一步將細胞打起繼代至飼養層細胞上並更換成2i-LIF培養系統，發現於第7天更換PGCM之col+組所形成之類EG colony顯著較多，第7及8天形成之類EG colony之PGC及分化多能性markers之表現與ES無異，以免疫螢光染色法分析後，發現皆有Oct4、Nanog、SSEA1及PGC-specific marker Stella之表現。綜上所述，血清飢餓及秋水仙素處理皆能夠顯著使NIH/3T3s與MEFs分別處於G0/G1及G2/M期，再進一步利用爪蟾蛋萃取物處理細胞週期一致化之細胞，發現秋水仙素處理NIH/3T3s可形成較多變為圓形之細胞，且其多能性Oct4及Nanog表現之細胞較多，而MEFs在經由爪蟾蛋萃取物處理後幾乎沒有變為圓形之細胞，而MEFs可否如NIH/3T3s一樣形成類EG細胞，需要進行試驗分析更準確找到其再程式化之時間，另外，第7天更換PGCM之col+之類EG colony形成效率顯著較高，且所有處理之類EG colony皆有PGC marker Stella及多能性markers Oct4、Nanog及SSEA1表現。

Cell cycle of donor cells would affect the efficiency of somatic cell nuclear transfer (SCNT), as well as the nuclear reprogramming efficiency. Recent researches have demonstrated that the Xenopus laevis egg extracts (XEE) treated cells, called extract treated cells (ETCs), could undergo reprogramming and regain the expressions of pluripotent genes, such as oct4, sox2 and nanog. Therefore, the aims of this study were to investigate the effects of cell cycle on the efficiency of reprogramming into the pluripotent stage by treating mouse somatic cells with XEE and assess the possibility to define the embryonic grem like (EG-like) cells from the reprogrammed cells. Experiment 1, a mouse NIH/3T3 cell line and mouse embryonic fibroblasts (MEFs) were incubated with 0.2% or 0.5% bovine serum (BS) for 3 or 5 days would significantly stay at G0/G1 phase, while NIH/3T3s and MEFs treated with various concentrations of colchicine (0.5, 1.0 or 1.5 μg/ml) for 1 or 2 days, would significantly stay at G2/M phase. Experiment 2, NIH/3T3s were treated 0.5% BS for 3 days or 0.5 μg/ml colchicine for 1 day before treatment with XEE. On Day 7 and 8 after XEE treatment, all groups showed the expressions of tumor suppressors (p53, p21 and p16), pluripotent markers (oct4, sox2 and nanog) and primordial germ cells (PGCs) markers (blimp1 and stella), although the expressions were low and unstable. However, there showed more round morphology cells, and the expressions of tumor suppressors, pluripotenct and PGC markers were increased in colchicine-treated NIH/3T3s. The expressions of Oct4 and Nanog protein were also shown by analysis of immunocytochemical (ICC) staining. MEFs treated with 0.2% BS for 5 days or 0.5 μg/ml colchicine for 2 days before XEE treatment showed pluripotent markers on Day 7 to Day 9, but the expressions of tumor suppressors, pluripotent and PGC markers still remained at low level. Furthermore, the expressions of PGC markers were low. Experiment 3, cell cycle-regulated NIH/3T3s were treated with XEE for 7 or 8 days, then incubated in PGCM for 24 h. For groups changed to PGCM on Day 7, colchicine-treated NIH/3T3s had significantly higher expressions of Blimp1, Stella and Sox2, while for groups changed to PGCM on Day 8, serum-starved NIH/3T3s had significantly higher expression of Blimp1. After cultured in PGCM for 24 h, the cells were passaged and seeded on feeder layer and then cultured in 2i-LIF culture system. It was found that groups changed to PGCM on Day 7, the colchcine group formed more EG-like colonies, although the expressions of pluripotent and PGC markers in the EG-like colonies showed no differences with ES cells in the goups changed to PGCM on Day 7 and Day 8. By analysis of immunocytochemistry, all groups of EG-like colonies expressed pluripotent markers, including Oct4, Nanog, SSEA1 and a PGC-specific marker Stella. These studies showed that after serum starvation and colchicine treatment, NIH/3T3s and MEFs could significantly stay at G0/G1 and G2/M, respectively. Further, we treated cell cycle-regulated cells by XEE, we found colchicine had more round morphology cells and Oct4/Nanog expressions in NIH/3T3s; but there were less round morphology cells and Oct4/Nanog expressions in MEFs. Then we changed to 2i-LIF culture system, the d7 colchicine formed more EG-like colonies, otherwise, all groups of colonies expressed PGC marker Stella and pluripotent markers Oct4, Nanog and SSEA1 in NIH/3T3s.

摘要------------------------------------------------------------------------------------------------ i -
目錄------------------------------------------------------------------------------------------------ v -
文獻探討 - 1 -
一、前言 - 1 -
二、分化之體細胞再程式化成多能性幹細胞（reprogramming of differentiated somatic cells into pluripotent stem cells） - 1 -
三、影響體細胞再程式化之因素 - 6 -
四、細胞週期調控因子之調控 - 8 -
五、腫瘤抑制因子誘導細胞老化（cellular senescence）及細胞凋亡（apoptosis）- 13-
六、細胞週期與腫瘤抑制因子對細胞多能性與再程式化之影響 - 15 -
七、再程式化細胞之基因表現狀態 - 16 -
八、結論 - 18 -
試驗一、不同濃度血清與秋水仙素處理小鼠體細胞、NIH/3T3細胞珠，對其細胞週期之影響 - 19 -
前言 - 19 -
試驗設計： - 21 -
材料與方法 - 21 -
一、不同濃度血清及秋水仙素處理小鼠體細胞----------------------------------------- 21 -
二、不同濃度血清及秋水仙素處理細胞之細胞週期及凋亡數----------------------- 23 -
三、 分析不同濃度血清及秋水仙素處理細胞之腫瘤抑制因子（tumor suppressors）之表現 - 24 -
結果與討論 - 28 -
一、細胞週期調控之NIH/3T3細胞株 - 28 -
二、細胞週期調控之MEFs - 29 -
結論--------------------------------------------------------------------------------------------- - 41 -
試驗二、利用爪蟾蛋萃取物處理細胞週期同期化之小鼠體細胞之再程式化效率--------------------------------------------------------------------------------------------------- - 42 -
前言--------------------------------------------------------------------------------------------- - 42 -
試驗設計： - 43 -
材料與方法 - 43 -
一、XEE之製備 - 43 -
二、XEE處理一致化細胞週期之小鼠體細胞 - 46 -
三、細胞處理XEE - 47 -
四、分析XEE處理停留於不同細胞週期之細胞後其分化多能性基因、腫瘤抑制因子（tumor suppressors）及PGC maker之表現 - 49 -
五、細胞免疫化學染色法ICC（immunocytochemical staining, ICC） - 51 -
六、統計分析 - 51 -
結果與討論 - 52 -
一、XEE處理經調控細胞週期之NIH/3T3s - 52 -
二、XEE處理經調控細胞週期之MEFs - 53 -
結論--------------------------------------------------------------------------------------------- - 67 -
試驗三、利用2i培養系統建立經XEE處理細胞轉變成類EG細胞 - 68 -
前言--------------------------------------------------------------------------------------------- - 68 -
試驗設計： - 69 -
材料與方法 - 69 -
一、2i-LIF培養系統培養ETC之EG-like細胞 - 69 -
二、細胞處理XEE - 70 -
三、分析不同細胞週期ETC於不同時間更換PGCM培養之PGC makers及分化多能性makers之表現 - 72 -
四、分析不同細胞週期ETC形成之類EG細胞之PGC及分化多能性makers之表現 - 73 -
五、統計分析 - 74 -
結果與討論 - 75 -
結論--------------------------------------------------------------------------------------------- - 84 -
總結--------------------------------------------------------------------------------------------- - 85 -
參考文獻 - 86 -

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