Prostaglandin E2 Regulates Liver versus Pancreas Cell-Fate Decisions and Endodermal Outgrowth

Abstract

SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen.

Cannabinoid receptor signaling regulates liver development and metabolism

“…EC signaling has previously been implicated in promoting trophoblast cell lineage differentiation (Sun et al, 2010) and neural development (Palazuelos et al, 2012;Psychoyos et al, 2012); one indication that Cnr signaling may also affect endodermal development and/or metabolic function was observed in Cnr1 −/− ob/ ob double-mutant mice, which exhibit growth retardation and exacerbated glucose intolerance (Li et al, 2013). The developmental phenotypes observed in Cnr mutant zebrafish support previously described liver abnormalities in Cnr knockout mice: the impact of Cnr activity on embryonic liver maturation might explain the delayed or aberrant hepatocyte proliferation and recovery of liver mass seen after partial hepatectomy in adult Cnr1 and Cnr2 knockout mice (Teixeira-Clerc et al, 2010), as the recapitulation of proliferation-promoting developmental pathways has been shown to be important during liver regeneration (Goessling et al, 2008;Nissim et al, 2014;Yin et al, 2012).…”

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

“…The mutants also exhibited decreased body weight and skin morphological and physiological defects. Additionally, prostaglandin signalling is implicated for its roles in a range of physiological processes such as cell fate decision (Nissim et al, 2014), cell differentiation (Li et al, 2000), and ciliogenesis (Jin et al, 2014). The inability of Plaa-null mice to survive, which may stem from impaired neuronal development in the brain, together with our findings that PGE 2 levels were significantly reduced in the brain and the lung of Plaa-null mouse embryos, raise the possibility that the pathogenesis of the condition we observed in PLAAdeficient mice and in patients with a non-functional PLAA could be a developmental defect caused at least partly by ineffective prostaglandin signalling.…”

Cell-based biological evaluations of 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent

“…20 The PGE 2 analogue dmPGE 2 is also currently in preclinical testing because it significantly increases HSC numbers. [2][3][4][5] We recently showed that 15-PGDH inhibitors elevate PGE 2 levels in A549 cells. 21 This result suggests that 15-PGDH inhibitors may have utility in the therapeutic management of diseases requiring elevated PGE 2 levels.…”

“…1 Recent studies have focused on EP2 and EP4 receptors because PGE 2 acts through these receptors to mediate regeneration and hematopoietic stem cell (HSC) development via the Wnt signaling pathway. [2][3][4][5] HSC homeostasis is tightly controlled by many factors, including growth factors, signaling molecules, and transcription factors. Recent studies have shown that PGE 2 regulates vertebrate HSC induction and engraftment.…”