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Review
. 2009 Jan 9;4(1):27-36.
doi: 10.1016/j.stem.2008.12.004.

Wnt-related molecules and signaling pathway equilibrium in hematopoiesis

Sachin Malhotra  1 , Paul W Kincade
Affiliations
Review

Wnt-related molecules and signaling pathway equilibrium in hematopoiesis

Sachin Malhotra et al. Cell Stem Cell. .

Abstract

There is near consensus that Wnt family molecules establish important gradients within niches where hematopoietic stem cells (HSC) reside. We review recent papers suggesting that a delicate balance is required between competing Wnt ligands and corresponding signaling pathways to maintain HSC integrity. Some steps in the transitions from HSC to lymphoid progenitor seem to be partially reversible and under the influence of Wnts. In addition, it has been recently suggested that HSC can oscillate between dormant versus active or lineage-biased states. We speculate that Wnts control a reflux process that may sustain stem cell self-renewal and differentiation potential.

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Figures

Figure 1
Figure 1. An Overview of the Wnt Family of Proteins and Three Signaling Pathways
The 19 Wnt ligands are recognized by cell surface receptors (Frizzled, LRP5/6, and ROR2). These receptor-ligand interactions induce many intracellular signaling/nuclear transcription events as indicated. Also shown are extracellular Wnt ligand modulators (sFRPs and WIF) and other Wnt receptor interacting ligands (R-spondin, Norrin, and Dkk).
Figure 2
Figure 2. Wnt Proteins Function in Equilibrium within Hematopoietic Stem Cell Niches
The net biological activity within a discrete marrow location is determined by factors related to synthesis, secretion, and presentation of multiple Wnt proteins as well as patterns of receptor expression on the hematopoietic cells. Functional gradients of these molecules are also determined by competition between them. Matrix-associated agonists and antagonists in the Wnt family are indicated in this model as blue and yellow, respectively. All of these parameters may need to be within carefully regulated ranges, and stem cells (HSC, depicted by gray shaded circles) can physically move into, within, and from niches. Dormant stem cells may preferentially associate with niches such as those provided by subendosteal osteoblasts. We speculate that a degree of reflux occurs as stem cells “test the waters” before either progressing in a blood cell lineage (shown by green shaded circles) or returning to a self-renewing or dormant state. That testing process might correspond to movement within a Wnt gradient followed by resettling in a niche. The only evidence for Wnt driven dedifferentiation comes from culture experiments as discussed in the text.
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