Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells

Charles Durand, Catherine Robin, Karine Bollerot, Margaret H Baron, Katrin Ottersbach, Elaine Dzierzak

Research output: Contribution to journalArticlepeer-review

Abstract

Hematopoietic stem cell (HSC) self-renewal and differentiation is regulated by cellular and molecular interactions with the surrounding microenvironment. During ontogeny, the aorta-gonad-mesonephros (AGM) region autonomously generates the first HSCs and serves as the first HSC-supportive microenvironment. Because the molecular identity of the AGM microenvironment is as yet unclear, we examined two closely related AGM stromal clones that differentially support HSCs. Expression analyses identified three putative HSC regulatory factors, beta-NGF (a neurotrophic factor), MIP-1gamma (a C-C chemokine family member) and Bmp4 (a TGF-beta family member). We show here that these three factors, when added to AGM explant cultures, enhance the in vivo repopulating ability of AGM HSCs. The effects of Bmp4 on AGM HSCs were further studied because this factor acts at the mesodermal and primitive erythropoietic stages in the mouse embryo. In this report, we show that enriched E11 AGM HSCs express Bmp receptors and can be inhibited in their activity by gremlin, a Bmp antagonist. Moreover, our results reveal a focal point of Bmp4 expression in the mesenchyme underlying HSC containing aortic clusters at E11. We suggest that Bmp4 plays a relatively late role in the regulation of HSCs as they emerge in the midgestation AGM.
Original languageEnglish
Pages (from-to)20838-43
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume104
Issue number52
DOIs
Publication statusPublished - 26 Dec 2007

Keywords

  • Animals
  • Aorta
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Cell Culture Techniques
  • Chemokines, CC
  • Embryonic Stem Cells
  • Gene Expression Regulation, Developmental
  • Gonads
  • Hematopoietic Stem Cells
  • Intercellular Signaling Peptides and Proteins
  • Macrophage Inflammatory Proteins
  • Mesonephros
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Nerve Growth Factor
  • Recombinant Proteins
  • Stromal Cells

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