Control of Hematopoietic Stem Cell Expansion by Inhibition of Axin Polymerization

Type of Award: Catalyst
Date Awarded: August 2014
Award End Date: July 2016
Amount Awarded: $ 200,000.00
PI(s): Zhijian Qian, PhD, UIC; Wei Du, PhD, UChicago;

Abstract: Cell based therapies represent promising treatment strategies for many diseases at the frontier of medicine and are often limited by the ability to generate sufficient amount of stem/progenitor cells. The beta-catenin signaling pathway is highly conserved between flies and mammalian systems and plays critical roles in controlling the self-renewal, proliferation, and differentiation of many types of stem/progenitor cells. However little is known of how the beta-catenin signaling can be controlled to specifically modulate stem/progenitor cell self-renewal and proliferation without affecting their differentiation. While null mutants of Drosophila Axin, a key negative regulator of beta-catenin pathway, affects both stem/progenitor cell self-renewal, proliferation, and differentiation, recent studies from the Du lab revealed that disrupting the DIX domain of Axin, which blocks Axin polymerization, only promoted stem/progenitor cell self-renewal, proliferation, but did not affect their differentiation. These observations suggest that inhibition of Axin polymerization can potentially be used to specifically control stem/progenitor cell self-renewal and proliferation without affecting their differentiation. This discovery sparked a new collaboration with the Qian lab at UIC, who has significant expertise studying the roles of the Wnt signaling in hematopoietic stem cells (HSCs). The new collaboration is aimed at developing a novel approach to modulate HSCs self-renewal and proliferation without affecting their differentiation. For this proposal, the Qian lab will generate a mouse model with Axin polymerization mutation in HSCs and will test the effects of disrupting Axin polymerization on HSC self-renewal, proliferation, and differentiation. The Du lab will develop high-throughput cell imaging based assays for Axin polymerization and will screen for compounds that can inhibit Axin polymerization. These studies will potentially lead to the identification of compounds that can promote the expansion of HSCs in vitro and improve clinical outcomes for HSC transplantation.