Stem cell fate: What a stem cell Wnts

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Activation of the Wnt signaling pathway in vivo leads to a loss of hematopoietic stem cell (HSC) differentiation and self-renewal potential.

Wnt signaling is well known for its involvement in development and pathogenesis. Previous studies have suggested that Wnt signaling plays a role in the renewal of the HSC population in the hematopoietic system, but the intracellular consequences resulting from the activation of the Wnt receptor Frizzled remain unclear. Binding of Wnt to Frizzled stabilizes β-catenin, which regulates expression of cell fate genes in a complex with Tcf-LEF transcription factors. Studies by Scheller et al. and by Kirstetter et al. in Nature Immunology now show that transgenic expression of a stable form of β-catenin blocks differentiation of murine HSCs.

To elucidate the consequences of conditionally overexpressed wild type β-catenin in mice, both groups designed a conditional expression system without retroviral or oncogenic components. In both studies, FACS analysis indicated that the differentiation of HSCs was arrested at early blood cell progenitor stages, leading to fatal anemia in the transgenic mice. Furthermore, failure of bone marrow engraftment by transformed HSCs in nude mice showed that the renewal potential of the HSCs was disrupted by β-catenin overexpression.

Using real-time polymerase chain reaction analysis, Kirstetter et al. discovered that the genes responsible for HSC population expansion (Cdkn1a, Hoxb4, and Bmi1) and myeloid progenitor formation (Sfp1) were significantly downregulated. However, the block of erythroid differentiation was due to ectopic PU.1 expression causing GATA-1 downregulation.

Scheller et al. in turn showed that transgenic HSCs had increased levels of cyclins E1 and E2 and reduced expression of the CDK inhibitory kinase p21^kip/waf, which is essential for maintaining resting HSCs. Thus, the presence of β-catenin enables HSCs to enter the cell cycle but depletes the stem cell reservoir, resulting in a loss of long-term engraftment capacity.

The differentiation blockage of transgenic HSCs shown in both studies is similar to the phenotype of leukemic cells, yet the exhaustion rather than the renewal of the HSC population indicates that Wnt signaling is not sufficient for leukemic transformation. As components of the Wnt pathway are upregulated in several types of leukemia, the results of these two studies may allow targeting leukemic cells without disturbing HSCs by altering the Wnt pathway. Future studies should elucidate more precisely the strength and duration of canonical Wnt signaling required for normal HSC functioning.

Mirko von Elstermann
Functional Glycomics Gateway

References

Kirstetter, P. et al. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nature Immunology 7, 1048 - 1056 (2006) | doi:10.1038/ni1381 | Article | PubMed |
Scheller, M. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nature Immunology 7, 1037 - 1047 (2006) | doi:10.1038/ni1387 | Article | PubMed |
Trowbridge, J. J., Moon, R. T., Bhatia, M. . Hematopoietic stem cell biology: too much of a Wnt thing. Nature Immunology 7, 1021 - 1023 (2006) | doi:10.1038/ni1006-1021 | Article | PubMed |