We have recently defined a novel hematopoietic stem cell population that is characterized by the lack of c-kit expression (receptor for steel factor, SLF). This stem cell population lacks the ability to radioprotect lethally irradiated mouse recipients (short term reconstituting cells, STRCs) and form splenic colonies when transplanted into lethally irradiated recipients. Furthermore, these cells do not proliferate in response to known hematopoietic growth factor (HGF) combinations. However, c-kit-negative stem cells can durably reconstitute the entire hematopoietic system when transplanted in vivo when co-transplanted with STRCs. We have proposed that steady state hematopoiesis is supported by pluripotential stem cells (PSCs) that express c-kit (c-kit+) and that c-kit negative cells are recruited into this actively contributing pool of stem cells to sustain hematopoietic growth and development. The survival, proliferation and differentiation of c-kit+ PSCs has been shown to be regulated by a complex network of hematopoietic growth (HGF) and inhibitory factors. In this regard, we have recently determined that IL-8 (chemokine family) and leukemia inhibitory factor (gp130 family) in combination with SLF can directly promote the growth of c-kit+ cells. Furthermore, we have shown that FLT-3-ligand can act as a survival factor for c-kit+ cells in the absence of cell division. We have also developed a novel non-viral molecular conjugate vector that specifically targets gene transfer to c-kit+ hematopoietic progenitor cells by incorporating SLF into the vector construction. This vector was shown to transduce greater than 95% of the target cell population and is versatile since vector targeting can be altered by the substitution of other ligands. Finally, using a c-kit+ multipotential stem cell line model that is highly representative of normal c-kit+ stem cells, we have identified novel cDNAs whose expression is induced and or regulated during the differentiation and commitment of c-kit+ multipotential cells to more committed progenitor cells using differential display RT PCR.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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