Article

Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration

Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Cell (Impact Factor: 33.12). 04/2009; 136(6):1136-47. DOI: 10.1016/j.cell.2009.01.015
Source: PubMed

ABSTRACT Interactions between developmental signaling pathways govern the formation and function of stem cells. Prostaglandin (PG) E2 regulates vertebrate hematopoietic stem cells (HSC). Similarly, the Wnt signaling pathway controls HSC self-renewal and bone marrow repopulation. Here, we show that wnt reporter activity in zebrafish HSCs is responsive to PGE2 modulation, demonstrating a direct interaction in vivo. Inhibition of PGE2 synthesis blocked wnt-induced alterations in HSC formation. PGE2 modified the wnt signaling cascade at the level of beta-catenin degradation through cAMP/PKA-mediated stabilizing phosphorylation events. The PGE2/Wnt interaction regulated murine stem and progenitor populations in vitro in hematopoietic ES cell assays and in vivo following transplantation. The relationship between PGE2 and Wnt was also conserved during regeneration of other organ systems. Our work provides in vivo evidence that Wnt activation in stem cells requires PGE2, and suggests the PGE2/Wnt interaction is a master regulator of vertebrate regeneration and recovery.

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Available from: Wolfram Goessling, Aug 24, 2015
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    • "We first tested whether genetically enhancing Wnt signaling by miR-99a;125b-2 could ameliorate pharmacologic Wnt inhibition. Treatment of MV4:11 cells with Wnt inhibitor ICG-001, which disrupts the b-catenin/CBP interaction (Emami et al. 2004), or the reversible COX inhibitor indomethacin (Indo), which suppresses b-catenin expression (Hawcroft et al. 2002; Goessling et al. 2009), reduced proliferation and colony-forming capacity while inducing apoptosis (Fig. 6A–C; Supplemental Fig. S6A–C). These effects were rescued by enforced expression of miR- 99a;125b-2 or shRNA-mediated knockdown of the miR- 125/let-7 common target APC (Fig. 6A–C; Supplemental Fig. S6A–C). "
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    ABSTRACT: Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.
    Genes & development 04/2014; 28(8):858-74. DOI:10.1101/gad.233791.113 · 12.64 Impact Factor
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    • "It is worth noting that in the zebrafish hematopoietic stem cells, PGE2 directly modulate the activity of the Wnt pathway. This direct PGE2/Wnt interaction, which is essential for liver and caudal fin regeneration in the adult zebrafish, is thus not restricted to the hematopoietic system and might be a shared property of regenerative tissues (Goessling et al., 2009). This induction of cell proliferation via apoptosis/PGE2 also exerts some unexpected effect on tumor cells. "
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    • "Importantly, in addition to roles in vasodilation, PGE2 has been found to inhibit macrophage maturation (Zaslona et al., 2012) and promote cell survival and expansion of HSPCs (Goessling et al., 2009, 2011; North et al., 2007). Upon binding to PGE2, the EP2 and EP4 Gα s protein-coupled receptors trigger an increase in intracellular cAMP levels (Regan et al., 1994) and amplify Wnt signaling activity via PKA-mediated stabilization of β-catenin (Goessling et al., 2009). In human cells, and perhaps at sufficiently high doses in rhesus macaque, PGE2 may regulate HSC cell survival and proliferation by impacting major regulators of HSC development, including RUNX1, LMO2, LY6A, HOXA9, CXCR4, FLT3, JAK1, CCR1, and CD8a, HHEX, JUNB, LCK, and TF (Goessling et al., 2009, 2011). "
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