Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Abstract

es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

New developments in neutrophil biology and periodontitis

“…Moreover, we unexpectedly discovered that the homeostatic function of developmental endothelial locus‐1 is not restricted to the regulation of neutrophil recruitment to peripheral tissues, but also involves the control of their progenitors in the bone marrow . We observed that developmental endothelial locus‐1 is expressed in the bone marrow with a spatial distribution that raised the possibility that developmental endothelial locus‐1 might be involved in the regulation of hematopoiesis.…”

“…We observed that developmental endothelial locus‐1 is expressed in the bone marrow with a spatial distribution that raised the possibility that developmental endothelial locus‐1 might be involved in the regulation of hematopoiesis. Specifically, we showed that developmental endothelial locus‐1 is expressed by arteriolar endothelial cells, a specialized mesenchymal stromal cell type designated CXCL12‐abundant reticular cells, and osteoblastic lineage cells, all of which are important components of the hematopoietic stem cell niche in the bone marrow . The niche provides a supportive micro‐anatomic environment for the hematopoietic stem cells as it maintains them in a quiescent state that reduces DNA damage and replicative senescence.…”

“…Moreover, the niche supports hematopoietic stem cell survival and renewal, and, upon demand, fosters stem cell proliferation and differentiation . We showed that, in the niche, developmental endothelial locus‐1 interacts with the alphavbeta3 integrin on hematopoietic stem cells and promotes their myeloid differentiation by regulating differentiation‐associated proliferation of long‐term hematopoietic stem cells . Briefly, developmental endothelial locus‐1 controls the numbers of mature myeloid cells (granulocytes and macrophages).…”

“…Briefly, developmental endothelial locus‐1 controls the numbers of mature myeloid cells (granulocytes and macrophages). The ability of developmental endothelial locus‐1 to enhance myelopoiesis occurs under both steady‐state and stress conditions, such as bacterial lipopolysaccharide‐induced systemic inflammation or after hematopoietic cell transplantation . Myeloid cell replenishment following lipopolysaccharide‐induced systemic inflammation as well as the bone marrow response to granulocyte colony stimulating factor administration failed in developmental endothelial locus‐1‐deficient mice as a result of diminished proliferation of hematopoietic stem and progenitor cells .…”

Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

“…The RNA from fluorescence-activated cell sorted endothelial cells was extracted with the RNeasy Plus Micro Kit (Qiagen, Hilden, Germany). cDNA was synthesized with an iScript cDNA Synthesis Kit (Bio-Rad Laboratories, Hercules, CA, USA), and mRNA expression levels for each gene were quantified by real-time quantitative PCR using SsoFast EvaGreen Supermix (Bio-Rad Laboratories) and a Bio-Rad Laboratories cycler system and gene-specific primers (Thermo Fisher Scientific) and normalization to Tbp (TATA-box binding protein) mRNA (31).…”