Canonical and noncanonical Wnt signaling in neural stem/progenitor cells.

The first mammalian Wnt to be discovered, Wnt-1, was found to be essential for the development of a large part of the mouse brain over 25 years ago. We have since learned that Wnt family secreted glycolipoproteins, of which there are nineteen, which activate a diverse network of signals that are particularly important during embryonic development and tissue regeneration. Wnt signals in the developing and adult brain can drive neural stem cell self-renewal, expansion, asymmetric cell division, maturation and differentiation. The molecular events taking place after a Wnt binds to its cell-surface receptors are complex and, at times, controversial. A deeper understanding of these events is anticipated to lead to improvements in the treatment of neurodegenerative diseases and stem cell-based replacement therapies. Here, we review the roles played by Wnts in neural stem cells in the developing mouse brain, at neurogenic sites of the adult mouse and in neural stem cell culture models.

Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.

Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34+ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a ß-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.