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| Hematopoietic stem cells: Wnt to be a stem cell?
Two studies reveal that Wnt signaling regulates hematopoietic stem cell self-renewal. Hematopoietic stem cells (HSCs) deriving from the bone marrow have the potential to develop into any type of blood cell. Although HSCs have been purified successfully and their phenotypic and functional properties are well characterized, the signals that control HSC self-renewal remain unclear. Wnt signaling plays fundamental roles in a plethora of developmental processes and has previously been implicated in stem cell proliferation. Two studies published in Nature now show that Wnt signaling also regulates HSC self-renewal.
Irving Weissman's group shows that the Wnt signaling pathway can induce proliferation of HSCs while inhibiting their differentiation, thereby resulting in self-renewal. Initially, they observed that overexpression of In parallel, Roel Nusse and colleagues have successfully isolated active Wnt proteins for the first time, a task that was formerly impaired by the low solubility of Wnt. Mass spectrometry on the proteins then revealed that they are palmitoylated on a conserved cysteine. Enzymatic removal of the palmitate or mutation of the cysteine resulted in a loss of Wnt signaling. Application of isolated Wnt to purified HSCs markedly increased cell proliferation, documenting Wnt's role in HSC self-renewal. These findings, as well as enhancing our understanding of Wnt post-translational modifications, document a role of Wnt signaling in HSC self-renewal. The data have possible implications for tissue engineering and bone marrow transplantation. The Wnt pathway is also closely linked to cancer lesions, which may involve deregulated self-renewal of cancer stem cells. Julia Howlett, Assistant Editor
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-catenin, a component of Wnt signaling, leads to dramatic expansion of an immature pool of HSCs in vitro. In vivo, HSCs respond to endogenous Wnt3a signaling during self-renewal. HSC growth is inhibited in vitro and shows reduced reconstitution in vivo when the Wnt inhibitors axin or a frizzled ligand-binding domain are ectopically expressed, demonstrating the physiological significance of this pathway. Furthermore, HoxB4 and Notch1 are upregulated in response to Wnt signaling in HSCs, raising the possibility that the effects of Wnt signaling on HSCs are mediated through these proteins.