Identifying hematopoietic stem cell proliferation genes for bone marrow transplantation

Bone marrow transplantation (BMT) has revolutionized the treatment of hematological malignancies and cancer treatments. BMT is the transplantation of hematopoietic stem cells (HSC) to reconstitute the blood system. High dose total body irradiation is used in traditional BMT to ablate the recipients' bone marrow with the belief that this frees the preoccupied stem cell niches. This ablation procedure causes severe side effects, and excludes older or weaker patients from these transplantation procedures. Therefore, nonablated BMT is highly desirable because of its reduced side effects. However, BMT without ablation in a murine model results in poor engraftment.; In this dissertation, the role of radiation in BMT was investigated with a novel transplantation procedure. Donor cell redistribution and proliferation in ablated and nonablated mice were compared by intraosseous implantation of donor cells. Our data indicated that radioablation affects HSC proliferation, rather than availability of HSC niches. Inefficient engraftment in nonablated BMT is the result of poor donor cell proliferation, rather than a lack of niche space. Competitive repopulation assays suggested that stem cell activity of donor cells was down-regulated in nonablated BMT recipients, and efficient engraftment is possible by manipulating HSC proliferation. Identifying genes involved in stem cell activity is Jiang Fan Zhong critical for manipulating HSC proliferation. Subsequently, genes involved in stem cell activity were identified by cDNA microarray profiling. Differential gene expression profiles were obtained from three bone marrow populations with similar immunophenotypes but different stem cell activity. Correlation of the differential gene expression pattern to the stem cell activity pattern was used as selection criteria for identifying genes involved in stem cell activity. Seventy-two potential stem cell activity related genes were identified. The expression patterns of these genes suggested that stem cell activity is maintained by orchestrated multiple gene interactions. Transcription factors among the potential stem cell related genes are candidates for stem cell proliferation manipulation.; This study suggests that the role of irradiation in BMT is stimulating HSC donor proliferation. The stem cell proliferation genes were identified by microarray profiling for HSC proliferation manipulation in this study. Efficient bone marrow transplantation in nonablated recipients can be achieved by manipulating stem cell proliferation genes.