Hematopoiesis is sustained throughout life by a specialized group of cells known as hematopoietic stem cells (HSC). Steady state hematopoiesis is maintained by a balanced supply of factors elaborated by the marrow microenvironment which can be broadly classified in two groups; positive regulators such as colony stimulating factors (CSF) and interleukins (IL), and negative regulators. Both types of factors are part of a complex regulatory network of hematopoiesis controlling viability, proliferation, differentiation and programmed cell death (apoptosis) of hematopoietic stem and progenitor cells. Mechanisms of how this network controls the recruitment of HSC into active phases of cell cycle are yet to be fully established. Adult bone marrow (BM), umbilical cord blood (CB) and mobilized peripheral blood (MPB) have all been identified as valuable sources of HSC. However, major differences in functional and behavioral properties of HSC obtained from adult BM, CB, and MPB, which may impact the clinical utility of these tissues, begin at an early stage of hematopoiesis, namely, hematopoietic stem and progenitor cell activation. To better characterize these differences, and to identify the most suitable stem cell population capable of restoring normal BM activities following HSC transplantation, the following hypotheses will be tested. (1) The investigators hypothesize that HSC isolated from BM, CB, and MPB differ in their ability to undergo ex vivo expansion due to intrinsic differences in their response to cytokine stimulation and its intracellular consequences, and that induction of proliferation of primitive HPC induces apoptosis which depletes HPC activity in a replication-associated manner. (2) The investigators hypothesize that CD34+ cells within the G0/G1 compartment of dormant HPC reside in opposing levels of dormancy and responsiveness to cytokine stimulation and that a balance between positive and negative regulators of hematopoiesis governs activation and inhibition of mitosis and apoptosis of these cells. Consequently, hematopoiesis is maintained through a process of instructive clonal activation (ICA) in which a network of feedback signals between differentiated progeny and receptive quiescent HPC play an important role in the recruitment of HSC into active phases of cell cycle. (3) The investigators propose that data generated from Specific Aims 1 and 2 could assist in formulating strategies aimed at achieving a high transduction efficiency of genetic material into HSC from all three tissues using retroviral mediated gene transfer. Testing of these hypotheses will contribute to the understanding of normal hematopoiesis and the mechanisms governing HSC activation and proliferation and will add to the knowledge of the biology of HSC and their successful use in the field of stem cell transplantation. Furthermore, such information will also provide the basis for advances in ex vivo expansion of stem cells and somatic gene transfer therapy.
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