Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells.

Yoshiko Matsumoto Ikushima, Fumio Arai, Kentaro Hosokawa, Hirofumi Toyama, Keiyo Takubo, Tomoyuki Furuyashiki, Shuh Narumiya, Toshio Suda

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Prostaglandin E(2) (PGE(2)) regulates hematopoietic stem/progenitor cell (HSPC) activity. However, the receptor(s) responsible for PGE(2) signaling remains unclear. Here, we identified EP4 as a receptor activated by PGE(2) to regulate HSPCs. Knockdown of Ep4 in HSPCs reduced long-term reconstitution capacity, whereas an EP4-selective agonist induced phosphorylation of GSK3β and β-catenin and enhanced long-term reconstitution capacity. Next, we analyzed the niche-mediated effect of PGE(2) in HSPC regulation. Bone marrow mesenchymal progenitor cells (MPCs) expressed EP receptors, and stimulation of MPCs with PGE(2) significantly increased their ability to support HSPC colony formation. Among the EP receptor agonists, only an EP4 agonist facilitated the formation of HSPC colonies after the coculture with MPCs. PGE(2) up-regulated the expression of cytokine-, cell adhesion-, extracellular matrix-, and protease-related genes in MPCs. We also examined the function of PGE(2)/EP4 signaling in the recovery of the HSPCs after myelosuppression. The administration of PGE(2) or an EP4 agonist facilitated the recovery of HSPCs from 5-fluorouracil (5-FU)-induced myelosuppression, indicating a role for PGE(2)/EP4 signaling in this process. Altogether, these data suggest that EP4 is a key receptor for PGE(2)-mediated direct and indirect regulation of HSPCs.

Original languageEnglish
Pages (from-to)1995-2007
Number of pages13
JournalBlood
Volume121
Issue number11
DOIs
Publication statusPublished - 2013 Mar 14

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Hematopoietic Stem Cells
Prostaglandins E
Stem cells
Mesenchymal Stromal Cells
Receptors, Prostaglandin E, EP2 Subtype
Catenins
Recovery
Phosphorylation
Coculture Techniques
Cell adhesion
Cell Adhesion
Fluorouracil
Extracellular Matrix
Peptide Hydrolases
Bone Marrow
Bone
Cytokines
Genes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells. / Ikushima, Yoshiko Matsumoto; Arai, Fumio; Hosokawa, Kentaro; Toyama, Hirofumi; Takubo, Keiyo; Furuyashiki, Tomoyuki; Narumiya, Shuh; Suda, Toshio.

In: Blood, Vol. 121, No. 11, 14.03.2013, p. 1995-2007.

Research output: Contribution to journalArticle

Ikushima, YM, Arai, F, Hosokawa, K, Toyama, H, Takubo, K, Furuyashiki, T, Narumiya, S & Suda, T 2013, 'Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells.', Blood, vol. 121, no. 11, pp. 1995-2007. https://doi.org/10.1182/blood-2012-06-437889
Ikushima, Yoshiko Matsumoto ; Arai, Fumio ; Hosokawa, Kentaro ; Toyama, Hirofumi ; Takubo, Keiyo ; Furuyashiki, Tomoyuki ; Narumiya, Shuh ; Suda, Toshio. / Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells. In: Blood. 2013 ; Vol. 121, No. 11. pp. 1995-2007.
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