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研究生:張毓翰
研究生(外文):Yuhan Chang
論文名稱:Gas7基因在人類骨髓間葉幹細胞分化之功能性研究
論文名稱(外文):The Functional Roles of Gas7 in the differentiation of Marrow Derived Human Mesenchymal Stem Cell
指導教授:趙清貴趙清貴引用關係
指導教授(外文):C. K. Chao
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
論文頁數:121
中文關鍵詞:間葉幹細胞軟骨細胞分化ERK1/2SOX9Gas7
外文關鍵詞:Mesenchymal stem cellChondrogenesisERK1/2SOX9Gas7
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間葉幹細胞,由於其具有多項潛能(multi-potential)與不易衰老的特性,因此成為組織工程的理想材料之一。間葉幹細胞的基礎研究,是組織工程技術的發展過程中必要的工作之一。Gas7是一個與細胞生長停滯 (growth-arrest)有關的基因。在文獻上已證實Gas7對於神經細胞的分化與生長扮演正面的功用性角色,並參與細胞骨架(Cytoskeleton)的重新排列。初步的研究也顯示,Gas7在雞胚胎軟骨發育過程亦有明顯的表現。本研究的目的在於探討Gas7在間葉幹細胞的分化為軟骨細胞的過程所扮演的角色。
研究的初期,我們由人體腸骨脊(iliac crest)取出的骨髓,分離出間葉幹細胞,並使用特定誘導培養基, 使其分化為軟骨細胞,骨細胞或脂肪細胞。建立一套誘導與評估間葉幹細胞分化能力的研究模式。研究的中期,我們測定Gas7在間葉幹細胞分化過程的表現情形。並將進一步藉由使用Gas7 anti-sense核苷酸,抑制Gas7表現,或藉由cDNA plasmid transfection 提昇Gas7表現量,觀察Gas7表現量的改變其對其細胞分化的影響。以更明確的釐清Gas7在間葉幹細胞軟骨分化上所扮演的角色。研究的後期,我們釐清Gas7與ERK1/2的關係,因為文獻上已證實ERK1/2在間葉幹細胞的分化過程扮演關鍵角色。此外我們進一步釐清Gas7與軟骨分化過程的主要基因SOX9的關係,並找出Gas7,ERK1/2與 SOX9三者之間的相對關係。
我們的研究結果顯示,Gas7在間葉幹細胞的分化為軟骨細胞的過程,Gas7的表現量會出現暫時性的上揚。藉由使用Gas7 anti-sense 核苷酸,能抑制Gas7表現,而且會抑制間葉幹細胞的分化為軟骨細胞。藉由Plasmid transfection 提昇Gas7表現量,並無法促進間葉幹細胞的分化為軟骨細胞。使用PD98059 (ERK1/2的活化抑制劑)抑制ERK1/2的活化或是使用SOX9 siRNA抑制SOX9的表現,均會抑制Gas7的表現而且也會延遲間葉幹細胞的分化為軟骨細胞;反之抑制Gas7的表現,並不會影響ERK1/2的活化或SOX9的表現。
我們的研究証實,Gas7在間葉幹細胞的分化為軟骨細胞的過程扮演不可或缺的關鍵性角色。而在此分化過程Gas7的表現可能直接或間接藉由ERK1/2-SOX9的訊息傳導來調控。
Mesenchymal stem cells (MSCs) have multiple differentiation potential in vitro and in vivo, can be cultured mitotically to expand these cells without the loss of their developmental potency, therefore, may play a role in the repair of bone or chondral defects. Before this possible application, understanding and development of the basic knowledge of MSCs differentiation is the essential work for the development of tissue engineering.
Growth arrest-specific (Gas) genes have been implicated in variety of biologic function, including the positive and negative control of cell cycle and apoptosis. Gas7 has been reported to be expressed in human neuroal cells and affects the growth of neurite. Gas7 gene is also expressed in the process of chondrogenesis in chicken embryo (Prof. Sue Lin Chao at Institute of Molecular Biology, Academia Sinica, Taiwan, personal communication).
The overall goal of this project is to investigate the role of Gas7 in the differentiation of hMSC.
In the very beginning, we established the methodology of isolating hMSCs from bone marrow aspirates obtaining from the iliac crest of volunteer donors. The chondrogenic, osteogenic or adipogenic differentiation of hMSCs was induced by special medium and we also established a quantification system for the evaluation of hMSCs chondrogenic, osteogenic or adipogenic capacities in vitro.
In the middle stage, we investigated the Gas7 expression profile during the process of chondrogenic differentiation. To assess whether Gas7 is necessary for hMSC differentiation, the expression of Gas7 was inhibited with antisense oligonucleotides or enhanced with Gas7 cDNA plasmid during hMSC chondrogenic differentiation. After the alternation of Gas7 expression, the chondrogenic capacities of hMSC were recorded.
In the final stage, we investigated the relationship between Gas7 and ERK1/2, the MAP kinase and SOX9 which have been identified in the involvement of hMSCs differentiation.
Our results revealed that the treatment of hMSCs with TGF-resulted in a transient up-regulation of hGas7b, one of the hGas7 isoforms (day 3 to day 5), a transient phosphorylation of ERK1/2 (0.5 h to 4 h) and an up-regulation of SOX9 (2 h to day 14). Transient expression of hGas7b was also detected in hMSCs by RT-PCR at day 2 and day 3 following TGF-1 treatment. Interference with hGas7b production by hGas7b-specific antisense oligonucleotide or inhibition of p-ERK with PD98059, a specific inhibitor of ERK signaling pathway, or interference with SOX9 production by SOX9 siRNA all caused adverse effects of chondrogenic differentiation of hMSCs. Meanwhile, inhibition of p-ERK or SOX9 both blocked the expression of hGas7b. However, the p-ERK and SOX9 pathway were not affected by inhibition of hGas7b.
In this study, we found that expression of Gas7 is potentially regulated by activation of ERK1/2 and SOX9, which are required for hMSC chondrogenesis. Taken together, these results suggest that Gas7 is required in chondrogenic differentiation of hMSCs, may be via an ERK1/2 pathway-regulated cytoskeletal reorganization.
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Table of Contents
中文摘要
Abstract (English)
Chapter 1 Introduction
1.1. Regeneration Medicine and Orthopaedic
1.2. Stem Cell and Regeneration Medicine
1.3. Marrow Derived Mesenchymal Stem Cells
1.4. Gas7

Chapter 2 The isolation and culture of human marrow-derived
mesenchymal stem cell
2.1. Materials and methods
2.1.1. Bone marrow aspiration
2.1.2. Isolation of bone marrow nucleated cells
Percoll
Ficoll
2.1.3. Surface marker of BM cells
2.1.4. Cytochemical staining of CFU-Fs
2.1.5. Cell proliferative capacity
2.1.6. Osteogenic, chondrogenic and adipogenic dfferentiation of CFU-Fs
2.1.7. Cytotoxicity of gradient medium
2.1.8. In vivo osteochondrogenic assay
2.1.9. Statistical analysis
2.2. Results
2.2.1. Characteristics of primary culture of human bone marrow cells
2.2.2. Percentage of CD166+/ CD34-, CD90+/ CD34-, SH3+/ CD34- and CD105+/CD34- cells in BM nucleated cells
2.2.3. Differentiational capacity of CFU-Fs
2.2.4. Cyto-toxicity of gradient medium
2.2.5. In vivo osteochondrogenic assay
2.3. Discussion


Chapter 3 The functional role of Gas7 in chondrogenesis of human marrow-derived mesenchymal stem cell

3.1. Materials and Methods
3.1.1. Isolation and Chondrogenesis of hMSCs
3.1.2. Inhibition of hGas7 expression
3.1.3. Overexpression of hGas7
3.1.4. Inhibition of the Activation of ERK1/2
3.1.5. Protein Isolation and Western Blot Analysis
3.1.6. Reverse Transcription (RT)-PCR
3.1.7. Inhibition of SOX9 expression
3.1.8. Quantification of Chondrogenic Capacity
3.1.9. Statistical Analysis
3.2. Results
3.2.1. Expression of hGas7 Is Required for the Chondrogenic
Differentiation of hMSCs
3.2.2. Overexpression of hGas7 Is Not Sufficient for
Chondrogenic Differentiation of hMSCs
3.2.3. Inhibition of ERK1/2 Activation or SOX9 Both Partially Inhibited
Gas7 Amplification in Chondrogenesis
3.3. Discussion
Chapter 4 Conclusion and Summary
Chapter 5 Future Work
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