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This dissertation, Effects of Intrinsic & Extrinsic Factors on the Growth and Differentiation of Human Mesenchymal Stem Cells by Jing, Li, 李靜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Effects of Intrinsic & Extrinsic Factors on the Growth and Differentiation of Human Mesenchymal Stem Cells Submitted by LI Jing for the degree of Doctor of Philosophy at the University of Hong Kong in October 2006 Mesenchymal stem cells (MSC) are important components of the bone marrow microenvironment and are progenitors of mesenchymal tissues. These cells play an important role in enhancing hematopoietic stem cell engraftment and reducing graft versus host disease in bone marrow transplantation (BMT). However, factors affecting the yield of bone marrow derived MSC remain unexplored. In addition, the response of MSC to either high dose chemotherapy or therapeutic irradiation was previously unknown. We compared the MSC, as represented by the colony forming unit-fibroblast (CFU-F) numbers derived from bone marrow samples of: 1) normal healthy donors of different ages; 2) healthy donors and patients with leukemia; 3) marrow harvested at st th th different time points (1, 10 & 20 aspiration) from the healthy donors; 4) marrow harvested by two kinds of needle from the same donor. There was no significant age-related difference of MSC yielded from donors younger than 50 years. The numbers of MSC retrieved from leukemic patients were significantly lower than those of normal donors. During the process of bone marrow harvesting for transplantation, the yield of MSC significantly decreased with repeated aspiration. However, there was no significant difference in terms of CFU-F number between the samples harvested by either conventional single end-holed needle or by specially designed multiple side holes needle. We investigated the in-vitro effects of single dose X-ray irradiation of therapeutic range (dosage range: 2, 4, 8, 12 Gy) on the proliferation and differentiation activities of human MSC (hMSC). Irradiation inhibited proliferation of hMSC up to 2 weeks post- irradiation but thereafter, those residual surviving cells regained their normal proliferation rate. Bone forming activity as reflected by alkaline phosphatase and calcium deposition was reduced in a dose-dependant fashion. Attempts to protect the irradiated cells with 1 μM all-trans retinoic acid did not show any beneficial effect on MSC proliferation and differentiation. We also assessed the acute direct effects of individual chemotherapeutic agents on hMSC. The chemosensitivity of hMSCs was determined by XTT assay in comparison with that of NB-4 cells, a leukemic cell line, and normal peripheral blood mononuclear cells. Human MSC were resistant to chemotherapeutic agents commonly used in BMT (i.e. busulfan, cyclophosphamide and methotrexate). However, they were relatively sensitive to a panel of cytotoxic agents such as paclitaxel, vincristine, cytarabine, cisplatin, daunorubicin, etoposide, topotecan and hydroxyurea. The inhibitory effect of paclitaxel and vincristine on MSC was particularly remarkable. We also found that there was sustained suppression in hMSC following 3 days exposure to paclitaxel, cytarabine, cisplatin, daunorubicin, etoposide, topotecan and hydroxyurea. However, significant recovery was seen in hMSC after treatment with dexamethasone or vincristine. In conclusion, bone marrow samples from donors younger than 50 years were equally good as MSC sources and the optimal bone marrow samples for M

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