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: 32.24). 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, Sep 28, 2015
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    • "Importantly, hematopoietic homeostasis was reestablished by stem and progenitor proliferation and differentiation over the course of 2 weeks, consistent with mammalian models. This same protocol was also utilized to evaluate conservation of HSC function for chemical screen hits between embryonic and adult zebrafish (Goessling et al., 2009; North et al., 2007). Further elevation of the radiation dose allowed hematopoietic regeneration by adult-to-adult HSC transplantation (Traver et al., 2003; Traver et al., 2004); this technique, an important therapeutic approach for leukemia and lymphoma, is used to determine the presence of a true long-lived multipotent HSC in mammalian models. "
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    ABSTRACT: Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future.
    Disease Models and Mechanisms 07/2014; 7(7):769-776. DOI:10.1242/dmm.016352 · 4.97 Impact Factor
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    • "Prostaglandin E2 is one such a molecule, as its production pathway is directly controlled by caspase-3 (Boland et al., 2013), and has a wide number of roles in regeneration and proliferation (Castellone et al., 2005; Goessling et al., 2009; Morata et al., 2011; Beaulieu et al., 2012; Boland et al., 2013). This effect is exerted through transient activation of the Wnt-β-catenin pathway via binding to members of the EP receptor family (Goessling et al., 2009). "
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    Frontiers in Physiology 04/2014; 5:149. DOI:10.3389/fphys.2014.00149 · 3.53 Impact Factor
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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.
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