Wnt Signals Hematopoietic Stem Cell Self-Renewal

Abstract

Two related articles demonstrate a role for Wnt signaling, which is involved in various developmental processes, in promoting hematopoietic stem cell (HSC) proliferation and self-renewal. HSCs comprise a self-renewing population of cells with the capacity to differentiate into all classes of differentiated blood cells. Clinically, HSCs are used to reconstitute the hematopoeitic systems of individuals undergoing blood and marrow transplants. The signals that regulate HSC self-renewal, however, have been unclear. Willert et al. expressed Wnt genes in various cell lines and purified secreted Wnt protein. Unexpectedly, the Wnt proteins, which promoted the proliferation and self-renewal of cultured HSCs, were hydrophobic, a property that depended on palmitoylation. Reya et al. discovered that constitutively active β-catenin (a downstream target of Wnt signaling) promoted the proliferation of phenotypically undifferentiated mouse HSCs in long-term culture and enhanced the expression of HoxB4 and Notch1, both of which have been implicated in HSC self-renewal. Cells expressing activated β-catenin reconstituted mouse hematopoeitic systems when transplanted in limiting numbers. The authors expressed a gene reporter in HSCs to show that Wnt signaling took place in transplanted HSCs during proliferation in vivo. Blocking Wnt signaling by inhibiting receptor binding attenuated HSC growth in vitro; ectopic expression of axin, which promotes β-catenin degradation, inhibited HSC growth in vitro and hematopoeitic reconstitution in vivo. Thus, Wnt signaling appears to play a key role in promoting HSC self-renewal. Wnt could potentially be used in vitro to expand human HSCs for use in transplantation. Moreover, the data suggest that aberrant Wnt signaling may play a role in HSC malignancies. K. Willert, J. D. Brown, E. Danenberg, A. W. Duncan, I. L. Weissman, T. Reya, R. Nusse, Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423 , 448-452 (2003). [Online Journal] T. Reya, A. W. Duncan, L. Ailles, J. Domen, D. C. Scherer, K. Willert, L. Hintz, R. Nusse, I. L. Weissman, A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423 , 409-414 (2003). [Online Journal]