Mechanisms of Synergistic Regulation of Stem/Progenitors

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DESCRIPTION (provided by applicant): Hematopoiesis is regulated by interacting cytokines that act on proliferation of hematopoietic stem cells (HSC) and myeloid progenitor cells (MPC) and on self-renewal of HSC. We identified novel selective actions in vitro and in vivo of IL-20 on proliferation of multipotential myeloid progenitor cells (CFU-GEMM) when used in combination with SCF, and have preliminary data showing IL-20 enhancement of competitive HSC in vivo. We believe that synergistic interactions are critical for normal maintenance and production of blood cells, and hypothesize that IL-20, alone or in combination with SCF, and perhaps other cytokines, will enhance proliferation of HSC and may be involved in the regulation of self-renewal of HSC. We consider cell cycle regulation and cell cycle checkpoints critical for correct regulation of proliferation and self-renewal of HSC, and hypothesize, based on our studies on SCF regulation of cell cycle asymmetry, and on p21cip1/waf1 monitoring of microtubule checkpoints, that the mitotic spindle assembly checkpoint (MSAC) is intimately involved in, and necessary for normal proliferation and self-renewal of HSC. We believe that the effects of p21cip1/waf1 on HSC, are at least in part mediated through the MSAC. We also hypothesize that the effects of IL-20, in combination with SCF on MPC and on HSC are mediated in part through p21cip1/waf1 and the MSAC. Our long term goals are to define cytokine effects that modulate proliferation and self-renewal of HSC for clinical benefit. Towards these goals we propose the following aims: 1. Evaluate effects of IL-20 and SCF, alone and in combination, on proliferation of HSC and MPC, and on self-renewal of HSC. 2. Determine mechanisms of action of IL-20 alone and in combination with other cytokines on cell proliferation and/or self-renewal of HSC and the potential roles of p21cip1/waf1, StatS, Wnt-GSK-3 pathway and SOCS in mediating these actions. 3. Elucidate the role of MSAC in proliferation of HSC and MPC, and in self-renewal of HSC, and link these effects to cytokine actions on these functions.