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Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells.

TitleDlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsMirshekar-Syahkal B, Haak E, Kimber GM, van Leusden K, Harvey K, O'Rourke J, Laborda J, Bauer SR, de Bruijn MFTR, Ferguson-Smith AC, Dzierzak E, Ottersbach K
JournalHaematologica
Volume98
Issue2
Pagination163-71
Date Published2013 Feb
ISSN1592-8721
KeywordsAnimals, Aorta, Cell Membrane, Core Binding Factor Alpha 2 Subunit, Embryo, Mammalian, Gene Expression, Gonads, Hematopoietic Stem Cells, Intercellular Signaling Peptides and Proteins, Mesonephros, Mice, Mice, Knockout, Muscle, Smooth, Vascular, Protein Transport, Sympathetic Nervous System
Abstract

The first mouse adult-repopulating hematopoietic stem cells emerge in the aorta-gonad-mesonephros region at embryonic day (E) 10.5. Their numbers in this region increase thereafter and begin to decline at E12.5, thus pointing to the possible existence of both positive and negative regulators of emerging hematopoietic stem cells. Our recent expression analysis of the aorta-gonad-mesonephros region showed that the Delta-like homologue 1 (Dlk1) gene is up-regulated in the region of the aorta-gonad-mesonephros where hematopoietic stem cells are preferentially located. To analyze its function, we studied Dlk1 expression in wild-type and hematopoietic stem cell-deficient embryos and determined hematopoietic stem and progenitor cell activity in Dlk1 knockout and overexpressing mice. Its role in hematopoietic support was studied in co-culture experiments using stromal cell lines that express varying levels of Dlk1. We show here that Dlk1 is expressed in the smooth muscle layer of the dorsal aorta and the ventral sub-aortic mesenchyme, where its expression is dependent on the hematopoietic transcription factor Runx1. We further demonstrate that Dlk1 has a negative impact on hematopoietic stem and progenitor cell activity in the aorta-gonad-mesonephros region in vivo, which is recapitulated in co-cultures of hematopoietic stem cells on stromal cells that express varying levels of Dlk1. This negative effect of Dlk1 on hematopoietic stem and progenitor cell activity requires the membrane-bound form of the protein and cannot be recapitulated by soluble Dlk1. Together, these data suggest that Dlk1 expression by cells of the aorta-gonad-mesonephros hematopoietic microenvironment limits hematopoietic stem cell expansion and is, to our knowledge, the first description of such a negative regulator in this tissue.

DOI10.3324/haematol.2012.070789
Alternate JournalHaematologica
PubMed ID22801971
PubMed Central IDPMC3561421
Grant List079249 / / Wellcome Trust / United Kingdom
095606 / / Wellcome Trust / United Kingdom
G0800784 / / Medical Research Council / United Kingdom
MR/J001597/1 / / Medical Research Council / United Kingdom
R37DK054077 / DK / NIDDK NIH HHS / United States
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