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研究生:彭宏智
研究生(外文):Hung-Chih Peng
論文名稱:探討轉染基因之間葉幹細胞促進骨髓基質微環境改變之機制
論文名稱(外文):Elucidation of the Mechanisms underlying the Microenvironmental Changes in Bone Marrow Stroma Induced by Exogenous Mesenchymal Stem Cells
指導教授:蘇瑀蘇瑀引用關係
指導教授(外文):Yeu Su
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:60
中文關鍵詞:骨質疏鬆症間葉幹細胞骨髓基質細胞鎖骨顱骨發育不全症骨分化
外文關鍵詞:osteoporosismesenchymal stem cellsbone marrow stromal cellscleidocranial dysplasia syndromeCbfa-1 (Runx2)CXCR4
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骨質疏鬆症為一常見的疾病,肇因於骨質重塑失衡,使骨骼變得較為脆弱而容易折斷。間葉幹細胞是成體幹細胞的一種,由於其不但容易被分離和培養而且具有多重分化的能力,因此已被用以治療包括移植體對抗宿主疾病 (GVHD) 在內的一些疾病。我們先前的研究發現,被 CXCR4 基因轉染的小鼠 C3H10T1/2 間葉幹細胞,經由靜脈注射後其返回以及滯留於骨髓的能力較佳,同時也發現當其經全身移植到糖皮質固醇誘發骨質疏鬆的 C3H/HeN 小鼠體內,較能促進骨質的回復。本研究主要目的在探討滯留在骨髓之移植幹細胞,其改善骨質的效果是否有部分是藉由改變骨髓內的微環境所造成。將 C3H/HeN 小鼠骨髓中的基質細胞分離後,在體外培養模擬骨髓的微環境,並與經轉錄因子 Cbfa-1 和 CXCR4 基因共同轉染的 C3H10T1/2 細胞進行共同培養,在十四天時發現鹼性去磷酸酶 (ALP) 的活性不再明顯降低,而骨髓基質細胞本身即表現高量的 ALP。此外,以反轉錄-聚合酶連鎖反應 (RT-PCR) 分析 Cbfa-1 或 CXCR4 基因轉染的 C3H10T1/2 細胞內一些與骨分化有關的基因,但發現 Wnts、TGFβ、FGF、PDGF、IL-6、CTGF、 VEGF 及 OPG 等具促進骨分化作用的基因表現沒有明顯增加情形。
Cbfa-1 為一促進間葉幹細胞分化成骨母細胞最關鍵的轉錄因子,已知其轉錄活性和穩定性會因泛素化及乙醯化而改變,當該基因發生突變使其轉錄活性降低,因而減少其促進骨分化的能力時,會造成鎖骨顱骨發育不全症 (CCD);本實驗室先前的研究結果顯示當 Cbfa-1 上位於24 的 lysine 被突變成 arginine;或位於 219及224的 lysine 被突變為 arginine 或 alanine;以及位於219和224的 lysine 被突變成 arginine 及 344和345 lysine 被突變成 alanine 時,不但其蛋白的穩定性會增加,並且更能促進C3H10T1/2 細胞之骨分化。在本研究中,我進一步製備了 Cbfa-1 之 Runt 區域內的 lysine (120、127、162、181和204) 以及 lysine 219或224 個別突變成 alanine 的 Cbfa-1,發現 Runt 區域內的 lysine 突變雖也導致其穩定性增加,但其促進 C3H10T1/2 細胞骨分化的能力,卻完全喪失,同時該蛋白之進核能力也大為降低。根據前述結果,我推測 Runt 區域不僅調控 Cbfa-1 的 DNA 結合與穩定性,其對該轉錄因子的進核的能力也有重要貢獻。
Osteoporosis is a common disease caused by an imbalanced bone remodeling which usually is associated with bone fragility and fracture. Mesenchymal stem cells are adult stem cells that can easily be isolated and cultured and can be induced to differentiate into different lineages. Hence, they have already been used for the treatment of graft-versus-host disease (GVHD). Our previous studies showed that CXCR4-overexpressing C3H10T1/2 cells had higher bone marrow homing and retention abilities and induced a better bone recovery, upon systemic transplantation in osteoporotic mice. One purpose of this study is to elucidate whether few engrafted MSCs could change the microenvironment of bone marrow to facilitate bone recovery. Isolated bone marrow stromal cells (BMSCs) were co-cultured with Cbfa-1 and CXCR4 co-expressing C3H101/2 cells. Even though basal expression of ALP was high in BMSCs, it was drastically decreased by the co-cultured with uninfected or LacZ infected C3H10T1/2 cells for 14 day. Surprisingly, I could not detect any increase in the expression of osteoblast differentiation-inducing factors such as Wnts, TGFβ, FGF2, PDGF, IL-6, CTGF, VEGF and OPG in Cbfa-1 or CXCR4-overexpressing C3H10T1/2 cells. Cbfa-1 is a key transcription factor for osteoblast differentiation whose stability and transcriptional activity are regulated by ubiquitination and acetylation. Indeed, mutation that inactivates this gene is a major cause of cleidocranial dysplasia (CCD) syndrome because of the failure of osteogenic differentiation of MSCs. Our previous studies showed that Cbfa-1 mutants (Cbfa-1K24R, Cbfa-1K219,224A and Cbfa-14PM) not only were more stable but also promoted stronger osteoblastic differentiation than their wild-type counterpart. To assess the contribution of other lysine residues of Cbfa-1 to its stability and transcriptional activity, I converted 5 lysine residues in the Runt domain (120, 127, 162, 181 and 204) as well as at positions 219 and 224 to alanines to obtain Cbfa-1RuntKA, Cbfa-1K219A and Cbfa-1K224A, respectively. While mutation of the Runt domain lysine residues also increased the stability of Cbfa-1, surprisingly I found the Runt domain mutant lose osteoblast differentiation-inducing ability completely. Finally, I also found that the nuclear localization ability of Cbfa-1RuntKA was markedly reduced. Taken together, my data suggest that the Runt domain of Cbfa-1 not only DNA binding and protein stability, but also nuclear translocation regulates of this transcription factor.
總目錄 ………………………………………………………………… 1
圖次目錄 ……………………………………………………………… 2
縮寫表 ………………………………………………………………… 4
英文摘要 ……………………………………………………………… 5
中文摘要 ……………………………………………………………… 6
緒論 …………………………………………………………………… 7
研究目的 ………………………………………………………………12
實驗設計 ………………………………………………………………14
材料方法 ………………………………………………………………16
實驗結果 ………………………………………………………………23
結果討論與未來工作 …………………………………………………27
參考文獻 ………………………………………………………………31
圖表 ……………………………………………………………………41
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