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研究生:施嵐馨
研究生(外文):Lan-Hsin Shih
論文名稱:Fhl1基因對骨母細胞的礦化作用及其可能對間質幹細胞的影響
論文名稱(外文):The effect of Fhl1 gene in osteoblast mineralization and the possible action in the differentiation of mesenchymal stem cells
指導教授:李互暉
指導教授(外文):Hu-Hui Lee
學位類別:碩士
校院名稱:國立嘉義大學
系所名稱:生物農業科技學系研究所
學門:農業科學學門
學類:農業技術學類
論文種類:學術論文
畢業學年度:102
語文別:中文
論文頁數:77
中文關鍵詞:Fhl1 基因雌激素骨母細胞間質幹細胞OCN基因OPN基因
外文關鍵詞:Fhl1estrogenOsteoblastMSCsOCNOPN
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FHL1 (Four and a half LIM domains 1) 基因為四個半的 LIM domain 所組成,屬於 LIM only protein family ,與調節基因的轉錄、細胞增殖、細胞分化還有細胞凋亡有關,目前也已知為一個抑癌基因。在先前文獻當中已知 FHL1 (人類基因寫法) 基因會大量表現在心肌和骨骼肌,同時已被證實會調節肌肉的生長與發育, FHL1 基因突變可能會造成不同的骨骼肌疾病,近年來更發現新的 FHL1 錯位突變 (missense mutation) 會造成身體攣縮,僵直性脊椎症候群 (rigid spine syndrome) 和肥厚性心肌病,但是卻沒有明顯的影響肌肉無力或萎縮,表示 FHL1 基因所造成的影響不局限於心肌和骨骼肌。在先前的研究當中也發現 FHL1 與雌激素有很大的關連性,在人類乳癌細胞 MCF7 當中, FHL1 會抑制雌激素下游的基因表現,但在肌肉當中正好相反,雌激素反而會抑制 Fhl1 (非人類基因寫法) 基因的表現。由於雌激素已知與骨骼健全有密切關係,停經婦女常因缺少雌激素而造成骨質疏鬆症,因此本試驗想要了解與雌激素有關聯的硬骨發育過程中, Fhl1 基因是否也參與調控。實驗結果發現,在小鼠的骨母前驅細胞 MC3T3-E1 細胞當中, Fhl1 基因的表現會隨著分化天數增加而增加,並且發現在處理雌激素之後, Fhl1 基因的表現會明顯受到誘導,同時 Fhl1 基因的表現亦會受到雌激素抑制劑 (ICI182780) 所抑制。為進一步了解 Fhl1 基因在骨母前驅細胞分化的影響,試驗利用 lentivirus 表現載體系統,將 Fhl1 基因大量表現在 MC3T3-E1 細胞當中,並誘導細胞分化,由 real-time PCR 檢測骨骼成熟標誌基因的表現,和 Alizarin red-S staining (ARS) 礦化染色和 cetylpyridinium chloride (CPC) 萃取分析量化結果皆可發現,大量表現 Fhl1 基因可明顯增加礦化,若使用 shRNA 將 Fhl1 基因表現抑制,則發現礦化情形會明顯受到抑制。另外我們想知道 Fhl1 基因對硬骨分化的影響會不會發生在更早期,例如骨骼細胞的分化命運尚未被決定的幹細胞階段,試驗將 Fhl1 基因同樣利用 lentivirus 感染的方式攜入間幹質細胞 mesenchymal stem cells (MSCs) 當中,同樣發現 Fhl1 基因在 MSCs 誘導硬骨分化時會隨著分化天數增加而增加,大量表現 Fhl1 基因則可明顯加速礦化,即使不同 Fhl1 isoforms 同樣都可以促使礦化增加。這表示 Fhl1 基因在硬骨分化過程中確實佔有重要的角色,並且在早期 MSCs 朝向硬骨發育時,即可影響硬骨的分化。
Four and a half LIM domains 1 (FHL1) belongs to a family of LIM-only proteins that regulate gene transcription, cell proliferation, differentiation and apoptosis. In addition, FHL1 has also been reported that plays a role in tumor suppression. FHL1 has been shown abundant expression in skeletal muscles and cardiac muscles, and has been verified regulating muscle growth and development. Recently, many different mutations in the FHL1 gene have been identified in human skeletal muscle diseases. However, a new missense mutation of FHL1 causes contracture, rigid spine syndrome, and hypertrophic cardiomyopathy, but affected individuals were not prominent in muscle weakness or atrophy, indicating that FHL1 may play roles not restricted to skeletal and cardiac muscles. Previous studies revealed that a relationship exists between FHL1 and estrogen, because FHL1 inhibits estrogen signaling in human breast cancer MCF7 cells, but estrogen represses Fhl1 expression in myoblast. Estrogen may regulate osseous metabolism by multiple mechanisms, and its aberrant action may result in bone diseases. It is known that estrogen deficiency is a major cause of postmenopausal loss of bone, leading to osteoporosis in aged women. Accordingly, I am interested to investigate the relationship between Fhl1 and estrogen in bone mineralization. My data show that the endogenous Fhl1 expression of the preosteoblastic cells, MC3T3-E1 is increased in the process of osteogenesis. Moreover, this expression status can be induced by estrogen and inhibited by estrogen inhibitor, ICI 182780. I also show that estrogen signaling as known knowledge can enhance osteoblast minerlization. Subsequently, I questioned whether the alteration of Fhl1 expression affects osteoblastic differentiation. I used the lentivirus expression system to transduce Fhl1 or shRNA of Fhl1 into MC3T3-E1 cells. I investigated the expression of osteoblastic markers, osteocalcin and osteopontin by real-time PCR, and examined the osteoblastic mineralization and quantitative calcium deposit by Alizarin red-S staining (ARS) and cetylpyridinium chloride assay (CPC) . It is concluded that the minerlization of MC3T3-E1 cells can be significantly enhanced by overexpressed Fhl1 and inhibited by decreased expression of Fhl1. Because the MC3T3-E1 cells have been determined to osteoblatic fate, then I questioned whether Fhl1 guides the flexible cell fate of mesenchymal stem cells toward osteoblast differentiation. Intriguingly, I found that increased Fhl1 expression, either Fhl1a or Fhl1b isoform, can also accelerated the osteogenesis of MSCs. Taken together of my data , I conclude that Fhl1 is an important factor to stimulate osteogensis in preosteoblastic or early stem cell stage.
摘要 1
Abstract 3
誌謝 5
第一章 前言 9
1-1 骨質重塑 (Bone remodeling) 9
1-2 雌激素與骨骼 (Estrogen and bone) 11
1-3 Wnt訊號與骨骼 (Wnt signaling and bone) 13
1-4 Four and a half LIM domain 1 (FHL1) 15
1-5 間質幹細胞朝向硬骨分化 (Mesenchymal stem cells
differentiation towards osteoblasts) 19
第二章 材料與方法 20
2-1 勝任細胞製備 (competent cell preparation) 20
2-2 細胞RNA萃取 Trizol 法 (RNA extraction- Trizol) 20
2-3 細胞RNA萃取 Solution D法 (RNA extraction- Solution D) 20
2-4 利用 RNA gel 量化檢測 RNA 品質
(Examine the RNA quality using RNA gel visualization) 21
2-5 DNase I處理 (DNase I treatment) 21
2-6 cDNA 製備 (cDNA preparation) 21
2-7 小量質體純化 (DNA mini-preparation) 22
2-8 大量質體純化 (DNA large-preparation) 22
2-9 Fhl1 cDNA 選殖 (Fhl1 cDNA cloning) 23
2-10 Fhl1A 基因構築 (pLKO-AS3W-tGFP-IRES-Fhl1A-His-myc construction) 23
2-11 Fhl1B 基因構築 (pLKO-AS3W-tGFP-IRES-Fhl1B- His-myc construction) 24
2-12 細胞轉型 (Competent cell transformation) 24
2-13 膠體電泳 (Agarose gel electrophoresis) 24
2-14 細胞培養液配置 (Cell culture medium preparation) 24
2-15 細胞解凍 (Cells defrost) 25
2-16 細胞培養 (Cell culture) 25
2-17 間質幹細胞 Mesenchymal stem cells (MSCs) 抽取
(Mesenchymal stem cells, MSCs preparation) 26

2-18 間質幹細胞 (MSCs) 初代培養與繼代 (MSCs primary culture
and subculture) 27
2-19 間質幹細胞 (MSCs) 細胞冷凍技術 (MSCs cell freezing) 27
2-20 細胞轉染 (Cell transfection) 28
2-21 慢病毒顆粒製備 (Lentivirus mediated production and
purification) 28
2-22 慢病毒感染細胞 (Lentivirus cell infection) 29
2-23 RNA干擾 (RNA Interference) 29
2-24 半定量PCR (Semi-quantitative PCR) 29
2-25 即時定量 PCR (Quantitative Real-time PCR, Q-PCR) 29
2-26 茜紅素染色 (Alizarin red S staining, ARS staining) 30
2-27 西吡氯銨定量 (cetylpyridinium chloride, CPC) 30
第三章 結果 31
3-1 MC3T3-E1 細胞分化過程中,內生性 Fhl1 基因表現量增加 31
3-2 MC3T3-E1 細胞分化過程中,內生性 Fhl1 基因表現受到17β-estradiol 所誘導,並受高濃度 estrogen inhibitor ,
ICI182780 所抑制 31
3-3 Overexpression of Fhl1 in MC3T3-E1 細胞可增加礦化 32
3-4 MC3T3-E1 細胞分化過程中,抑制內生性 Fhl1 基因表現,
使 MC3T3-E1 細胞礦化受到抑制 33
3-5 提高病毒轉染效率測試- polybrene (hexadimethrine bromide)
與 protamine sulfate 藥劑之比較 34
3-6 MSCs 硬骨分化中,內生性 Fhl1 基因表現量增加 35
3-7 Overexpression of Fhl1 in MSCs 可增加礦化 36
3-8 Fhl1a 與 Fhl1b isoforms 在 MSCs 在硬骨分化中影響
之比較 36
第四章 討論 38
第五章 附圖及附表 48
表格 1. Real-time PCR 所使用之 primer (5’to 3’) 48
表格 2. RNA interference 序列 49
圖 1. Fhl1 及成骨作用過程後期表現的分化基因 OCN 及 OPN
在 MC3T3-E1 細胞分化中的表現量變化 50
圖 2. MC3T3-E1 細胞處理 17β-estradiol 和不同濃度之 estrogen
inhibitor (ICI182780) 之內生性 Fhl1 基因及成骨作用
分化基因 OCN 及 OPN 基因之表現 51

圖 3. ARS 染色 MC3T3-E1 細胞處理 17β-estradiol 和不同濃度之 estrogen inhibitor (ICI182780) ,並且 ARS 染色結果以
CPC assay 量化 52
圖 4. pLKO-AS3W-eGFP 和 pLKO-AS3W- Fhl1-IRES-tGFP構築
設計與 MC3T3-E1 細胞 pLKO-AS3W-eGFP 和 pLKO-
AS3W- Fhl1-IRES-tGFP 螢光表現 53
圖 5. 利用慢病毒 (lentivirus) 載體 overexpression Fhl1 在
MC3T3-E1 細胞之 real-time PCR 分析量化圖 54
圖 6. 利用慢病毒 (lentivirus) 載體 overexpression Fhl1 基因在 MC3T3-E1 細胞之 ARS 染色和 CPC assay 將 ARS 染色
結果量化 55
圖 7. 利用慢病毒 (lentivirus) 載體攜帶 shRNA 抑制內生性 Fhl1
基因表現在 MC3T3-E1 細胞之 real-time PCR 分析量化圖 56
圖 8. 利用慢病毒 (lentivirus) 載體將 sheGFP 和 shFhl1 表現在 MC3T3-E1 細胞之 ARS 染色和 CPC assay 將 ARS 染色
結果量化 57
圖 9. 不同濃度 polybrene 與 protamine 陽離子藥劑之比較 58
圖 10. 不同濃度 polybrene 與 protamine 陽離子藥劑對 MSCs 硬
骨分化之比較 ARS 染色圖 59
圖11. Fhl1 基因及成骨作用過程後期表現的分化基因 OCN 及
OPN 基因在 MSCs 硬骨分化不同天數中之表現量變化 60
圖 12. MSCs 硬骨分化不同天數之 ARS 染色圖和 CPC assay 將
ARS 染色結果量化 61
圖 13. MSCs pLKO-AS3W-eGFP 和 pLKO-AS3W- Fhl1-IRES-tGFP
螢光表現與明視野 MSCs 細胞狀況 62
圖 14. 利用 lentivirus 載體在 MSCs 過度表現 Fhl1 基因 63
圖 15. Fhl1a 與 Fhl1b isoforms 在 MSCs 在硬骨分化中影響之比較 64
引用文獻 65
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