지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
논문 기본 정보
- 자료유형
- 학위논문
- 저자정보
- 지도교수
- 김승후
- 발행연도
- 2013
- 저작권
- 울산대학교 논문은 저작권에 의해 보호받습니다.
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초록· 키워드
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Novel therapeutic approaches using human mesenchymal stem cells (MSCs) have yielded promising results. However, these approaches have confronted with lots of limitation and hurdles on the way to clinic thus far. Development of cellular senescence with passing for in vitro expansion which is predetermined to obtain sufficient cells for clinical application is one of the major obstacles and therefore considerable efforts have been directed at evading cellular senescence with long-term culture.
A senescent cells has undergone widespread changes in protein expression and secretion, ultimately develops senescence-associated secretory phenotype (SASP). However, little is known about the mechanisms regulating SASP and its function with respect to cellular senescence. Therefore, understanding the nature of SASP and its role in the regulation of cellular senescence in stem cells is prerequisite to the development of stem cell based therapy.
In our study, mononocyte chemoattractant protein-1 (MCP-1) is major SASP in aging human MSCs and augments cellular senescence through its receptor chemokine c-c motif receptor 2 (CCR2), which is accompanied by an increase in the protein P-p53 and p21 through the action on ROS/p38MAPK signaling. It is intriguing to note that secreted MCP-1 also induce paracrine senescence as well as autocrine effects on senescent cells with positive feedback loop.
Successful completion of the described studies will provide groundwork for further pharmacologic and genetic manipulation of adult stem cells aimed at developing more efficient modalities for stem cell based therapy.
A senescent cells has undergone widespread changes in protein expression and secretion, ultimately develops senescence-associated secretory phenotype (SASP). However, little is known about the mechanisms regulating SASP and its function with respect to cellular senescence. Therefore, understanding the nature of SASP and its role in the regulation of cellular senescence in stem cells is prerequisite to the development of stem cell based therapy.
In our study, mononocyte chemoattractant protein-1 (MCP-1) is major SASP in aging human MSCs and augments cellular senescence through its receptor chemokine c-c motif receptor 2 (CCR2), which is accompanied by an increase in the protein P-p53 and p21 through the action on ROS/p38MAPK signaling. It is intriguing to note that secreted MCP-1 also induce paracrine senescence as well as autocrine effects on senescent cells with positive feedback loop.
Successful completion of the described studies will provide groundwork for further pharmacologic and genetic manipulation of adult stem cells aimed at developing more efficient modalities for stem cell based therapy.
목차
ABSTRACT iTABLE OF CONTENTS iiiLIST OF FIGURES vINTRODUCTION 1MATERIALS AND METHODS1. UCB harvest 32. MSCs isolation and expansion 33. Overexpression and activation of p53 44. Cell growth 45. In vitro muli-lineage differentiation 56. Evaluation of multi-lineage differentiation potential 67. Flow cytometry 78. Cytokine antibody array and ELISA 89. Real time PCR and siRNA 810. Senescence-associated beta- galactose staining (SA-β gal staining) 911. Telomerase activity assay 912. Western blot 1013. Statistical analysis 10RESULTS1. Characterization of UCB-MSCs 122. Long term expansion induced cellular senescence 133. Cellular senescence altered the property of stem cell 144. Long term cultivation changed the secretome of MSCs 155. Treatment of MCP-1 augmented senescence of UCB-MSCs 176. Silencing of MCP-1 delayed senescence of UCB-MSCs 187. CCR2 expression is up-regulated in UCB-MSCs with passing and CCR2blockade mitigates the progress of senescence 198. MCP-1secretion through CCR2 drive auto/paracrine senescence of UCB-MSCs inpositive feedback loop 209. ROS and p38MAPK pathway mediate MCP-1 provoked senescence signaling inUCB-MSCs 22DISCUSSION 51REFEREBCES 57국문요약 64
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