Hematopoiesis occurs in a complex microenvironment made up of a variety of non-hematopoietic cells including endothelial cells, stromal cells and adipocytes. These accessory cells provide regulatory signals, in the form of positive and negative growth factors and adhesive molecules, which affect the survival, proliferation and differentiation of hematopoietic stem and progenitor cells. Although a large number of hematopoietic growth factors have been identified, no combination of these factors has been shown to maintain/expand the reconstituting capacity of stem cells over an extended period of time in vitro in the absence of adhesion to microenvironment cells. Thus, analysis of blood cell formation in the context of these microenvironment cells provides additional and important information concerning the regulation of hematopoiesis. It is also increasingly clear that multiple aspects of hematopoiesis are controlled by key transcription factors. However, less well studied is how the interaction of growth factors presented in the microenvironment with growth factor receptors and other cell-cell interactions modulate transcription factor function, and thus ultimately control blood formation under physiologic conditions or in response to commonly encountered stress situations. One essential growth factor that is expressed in the hematopoietic microenvironment (HM) is stem cell factor (SCF); the interaction of SCF with the receptor tyrosine kinase, c-kit, plays a critical role in both erythroid and mast cell production in vivo, as demonstrated by the phenotypic abnormalities seen in mouse mutants of the genes encoding SCF (Steel) and c-kit (Dominant white spotting) mice. In addition, c-kit is expressed on both hematopoietic stem cells and multilineage progenitor cells. SCF is expressed as both soluble and membrane bound isoforms in the HM. During the previous funding period, the PI's laboratory has shown in vitro and in vivo evidence that distinct isoforms of SCF produce different cellular responses in several c-kit+ cell populations. The overall hypothesis to be tested in the proposed research utilizing transgenic and """"""""knock-in"""""""" mice is that the biological effects of SCF are due, in part, to the adhesion of cells within the HM and the interaction of c-kit+ with cell-associated SCF, which influences the duration of activation of c-kit and downstream signaling in these cells.
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