Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells.
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.
Durand
Charles
C
Department of Cell Biology and Genetics, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
Robin
Catherine
C
Bollerot
Karine
K
Baron
Margaret H
MH
Ottersbach
Katrin
K
Dzierzak
Elaine
E
D000818:Animals; D001011:Aorta / Q000196:embryology / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D018929:Cell Culture Techniques; D019742:Chemokines, CC / Q000378:metabolism; D016207:Cytokines; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006066:Gonads / Q000196:embryology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008650:Mesonephros / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D017154:Stromal Cells / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D019742:Chemokines, CC; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D020932:Nerve Growth Factor; D011994:Recombinant Proteins; C525810:Bmp4 protein, mouse; C095218:Ccl9 protein, mouse; C113178:Grem1 protein, mouse