Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols

Timo Frömel, Benno Jungblut, Jiong Hu, Caroline Trouvain, Eduardo Barbosa-Sicard, Rüdiger Popp, Stefan Liebner, Stefanie Dimmeler, Bruce D. Hammock, Ingrid Fleming

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Fatty acid epoxides are important lipid signaling molecules involved in the regulation of vascular tone and homeostasis. Tissue and plasma levels of these mediators are determined by the activity of cytochrome P450 epoxygenases and the soluble epoxide hydrolase (sEH), and targeting the latter is an effective way of manipulating epoxide levels in vivo. We investigated the role of the sEH in regulating the mobilization and proliferation of progenitor cells with vasculogenic/reparative potential. Our studies revealed that sEH down-regulation/inhibition impaired the development of the caudal vein plexus in zebrafish, and decreased the numbers of lmo2/cmyb-positive progenitor cells therein. In mice sEH inactivation attenuated progenitor cell proliferation (spleen colony formation), but the sEH products 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) and 11,12- dihydroxyeicosatrienoic acid stimulated canonicalWnt signaling and rescued the effects of sEH inhibition. In murine bone marrow, the epoxide/diol content increased during GCSF - induced progenitor cell expansion and mobilization, and both mobilization and spleen colony formation were reduced in sEH -/-mice. Similarly, sEH -/- mice showed impaired functional recovery following hindlimb ischemia, which was rescued following either the restoration of bone marrow sEH activity or treatment with 12,13-DiHOME. Thus, sEH activity is required for optimal progenitor cell proliferation, whereas long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization, and vascular repair.

Original languageEnglish (US)
Pages (from-to)9995-10000
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number25
DOIs
StatePublished - Jun 19 2012

Keywords

  • Beta-catenin
  • Ischemic hindlimb
  • Linoleic acid

ASJC Scopus subject areas

  • General

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    Frömel, T., Jungblut, B., Hu, J., Trouvain, C., Barbosa-Sicard, E., Popp, R., Liebner, S., Dimmeler, S., Hammock, B. D., & Fleming, I. (2012). Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols. Proceedings of the National Academy of Sciences of the United States of America, 109(25), 9995-10000. https://doi.org/10.1073/pnas.1206493109