stem cell signaling

stem cell signaling - Vol 447 | 21 June 2007 |...

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LETTERS Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis Trista E. North 1,2 , Wolfram Goessling 1,2 , Carl R. Walkley 1,3 , Claudia Lengerke 1 , Kamden R. Kopani 1,2 , Allegra M. Lord 1,2 , Gerhard J. Weber 1,2 , Teresa V. Bowman 1,2 , Il-Ho Jang 1 , Tilo Grosser 4 , Garret A. FitzGerald 4 , George Q. Daley 1 , Stuart H. Orkin 1,2,3 & Leonard I. Zon 1,2 Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta– gonad–mesonephros region subsequently colonize fetal and adult haematopoietic organs 1,2 . To identify new modulators of HSC formation and homeostasis, a panel of biologically active com- pounds was screened for effects on stem cell induction in the zebrafish aorta–gonad–mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stemcelldifferentiationassays,PGE2causedamplificationofmulti- potent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post trans- plant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution compet- itive transplantation. The conserved role for PGE2 in the regu- lation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes. A chemical genetic screen was conducted to identify new pathways modulating definitive HSC formation during zebrafish embryogen- esis. runx1 and cmyb , required for mammalian HSC development, are expressed in the ventral wall of the dorsal aorta in a region ana- logous to the mammalian aorta–gonad–mesonephros (AGM) at 36 h post fertilization (h.p.f.) 3–5 . Wild-type embryos, incubated with indi- vidual chemicals, were examined for alterations in runx1 1 / cmyb 1 HSCs by in situ hybridization expression at 36 h.p.f. A high percent- age of compounds (91.7%, 2,275 of 2,357) failed to alter HSC express- ion, whereas 35 (1.4%) and 47 (1.9%) led to increased or decreased numbers of HSCs, respectively. Among these substances, 10 affected the prostaglandin pathway (Supplementary Table 1). runx1 1 / cmyb 1 HSCs comprise a line of flattened endothelial cells (arrow) and hae- matopoietic clusters (arrowhead) in the aorta (Fig. 1a–c); linoleic acid increased HSC numbers (22 altered out of 30 scored), whereas celecoxib, a cyclooxygenase (Cox)2 inhibitor, decreased HSCs (26/ 31). PGE2 is the main effector prostanoid produced in the zebrafish 6 and is regulated by both Cox1 (also known as Ptgs1) and Cox2 (also known as Ptgs2a). Treatment of zebrafish embryos with PGE2 increased expression of runx1 / cmyb (25/49), whereas Cox inhibition with SC560 (Cox1) and NS398 (Cox2) (Supplementary Fig. 1a–e)
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This note was uploaded on 04/26/2010 for the course SCI 35254 taught by Professor George during the Spring '10 term at Aarhus Universitet.

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stem cell signaling - Vol 447 | 21 June 2007 |...

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