Dissertation
Dissertation > Medicine, health > Basic Medical > Pathology > Pathophysiology

Damage and Apoptosis Mechanism in Bone Marrow-derived FIK-1~+MSCs Induced by Chemotherapeutic Agents

Author LuChunHua
Tutor ZhaoChunHua
School Beijing Union Medical College
Course Internal Medicine
Keywords mesenchymal stem cells apoptosis TAp63a p53 cisplatin DNA damage etoposide senesencse
CLC R363
Type PhD thesis
Year 2008
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Mesenchymal stem cells(MSCs)are multipotential cells that can be isolated from various of human tissues such as bone marrow, adipose tissue, muscle, brain and dermis of mammalian. They are able to be expensively expended in vitro and differentiate into osteocytes, chondrocytes, adipocytes, myocytes and even neural cells under appropriate conditions. Recently, more and more attentions are paid to MSCs for their potential roles in treatment of varieties of diseases including neural degenerative disorder, acute myocardial infarction, autoimmunologic diseases and GVHD after haemopoietic stem cells transplantation.These potential clinical applications have encouraged us a lot, but it still remains largely unclear as to whether DNA damage could affect the function of bMSCs and the mechanism of apoptosis under the influence of chemotherapeutic agents.First part we discussed the response of bMSCs to chemotherapeutic agents induced damage. We found that the phenotype and differentiation potential of hMSC were not altered by genotoxic treatment at clinically relevant conditions in vitro; but senescence index increased significantly after long and persistant exposoure. Apotosis was detected to be associated with longer exposoure time and higher concentration. Chemotherapeutic treatments did result in an over-expression of p53 protein but this increase is not accompany with the appearance of cell apoptosis; P63, a member of p53 family, is similar to p53 in configuration and function. Endogenous TAp63αwas induced by chemotherapeutic agents, probably indicating that its expression was correlated with apoptosis.Second part discussed TAp63a induced apoptosis in bMSCs treated with chemotherapeutic agents. By using the method of RNAi we aquired knocking down of TAp63ain bMSCs were stabley and efficiently, which did not change cell cycle distributions and growth curve. TAp63a RNA interference led to drug resistance to chemotherapeutic agents cisplatin and etoposide significantly which was accompanied by decreased apoptosis. The downstream targets were also investigated. The expression level of proapoptotic members Bax and caspase 3 were reduced with decreased TAp63a protein. These results provide new evidence that TAp63a could induce apoptosis under the treatment of chemotherapeutic agents in bMSCs.

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