Ebf3 niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells.

Lympho-hematopoiesis is regulated by cytokines; however, it remains unclear how cytokines regulate hematopoietic stem cells (HSCs) to induce production of lymphoid progenitors. Here, we show that in mice whose CXC chemokine ligand 12 (CXCL12) is deleted from half HSC niche cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, HSCs migrate from CXCL12-deficient niches to CXCL12-intact niches. In mice whose CXCL12 is deleted from all Ebf3/leptin receptor (LepR) CAR cells, HSCs are markedly reduced and their ability to generate B cell progenitors is reduced compared with that to generate myeloid progenitors even when transplanted into wild-type mice.

EHBP1L1, an apicobasal polarity regulator, is critical for nuclear polarization during enucleation of erythroblasts.

Cell polarity, the asymmetric distribution of proteins and organelles, is permanently or transiently established in various cell types and plays an important role in many physiological events. epidermal growth factor receptor substrate 15 homology domain-binding protein 1-like 1 (EHBP1L1) is an adapter protein that is localized on recycling endosomes and regulates apical-directed transport in polarized epithelial cells. However, the role of EHBP1L1 in nonepithelial cells, remains unknown.

Identification of CXCL12-abundant reticular cells in human adult bone marrow.

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described.

Niches for hematopoietic stem cells and immune cell progenitors.

The special microenvironments, termed niches, with which hematopoietic stem cells (HSCs) are in contact, have been thought to be required for the maintenance of HSCs and the generation of immune cells in bone marrow. Although the identity of the HSC niche has been a subject of long-standing debate, recent findings demonstrate that a population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing (LepR+) cells, are the major cellular components of niches for HSCs and lymphoid progenitors, which express specific transcription factors, including Foxc1 and Ebf3, and cytokines, including CXCL12 and stem cell factor (SCF), essential for their niche functions. The identity and functions of other types of cells, including osteoblasts, sinusoidal endothelial cells, periarteriolar cells, megakaryocytes and a population of macrophages in HSC maintenance, have also been shown.

Numerous niches for hematopoietic stem cells remain empty during homeostasis.

Hematopoietic stem cells (HSCs) reside in and are maintained by special microenvironments, termed niches. It is assumed that the HSC niche space remains occupied by endogenous cells and that myelosuppressive conditioning is required to achieve high levels of HSC engraftment. We herein demonstrate that upon the transplantation of very large numbers of purified HSCs into normal mice not exposed to myeloablation, donor HSCs engrafted in niches distant from filled HSC niches without replacing host HSCs and subsequently proliferated and generated hematopoietic progenitors, leading to marked increases in the overall HSC numbers in bone marrow.

Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation.

Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis.

CXCL12 catches T-ALL at the entrance of the bone marrow.

A fraction of patients with T-cell acute lymphoblastic leukemias (T-ALLs) relapse and have a dismal prognosis. Two recent papers in Cancer Cell reveal that endothelial cell-derived CXCL12 is essential for bone marrow involvement and tumor progression in T-ALL patients, suggesting that this chemokine axis presents a potential therapeutic target for the treatment of T-ALL.

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12.

Hepatic expression levels of CXCL12, a chemokine important in inflammatory and stem cell recruitment, and its receptor, C-X-C chemokine receptor 4, are increased during all forms of liver injury. CXCL12 is expressed by both parenchymal and nonparenchymal hepatic cells, and on the basis of immunohistochemistry, biliary epithelial cells (BECs) are thought to be a predominant source of hepatic CXCL12, thereby promoting periportal recruitment of C-X-C chemokine receptor 4-expressing lymphocytes. Our study aims to show that BECs may, in fact, not be the predominant source of hepatic CXCL12.

Myeloid cells stimulate their progenitors in an emergency.

The nature and functions of cells creating hematopoietic niches during inflammation remain incompletely understood. In this issue of Immunity, Kwak et al. (2015) reveal that myeloid cell-produced reactive oxygen species stimulate proliferation of myeloid progenitors establishing an additional mechanism to regulate hematopoiesis.

Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation.

Haematopoietic stem and progenitor cells are maintained by special microenvironments known as niches in bone marrow. Many studies have identified diverse candidate cells that constitute niches for haematopoietic stem cells in the marrow, including osteoblasts, endothelial cells, Schwann cells, α-smooth muscle actin-expressing macrophages and mesenchymal progenitors such as CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, stem cell factor-expressing cells, nestin-expressing cells and platelet-derived growth factor receptor-α (PDGFR-α)(+)Sca-1(+)CD45(-)Ter119(-) (PαS) cells. However, the molecular basis of the formation of the niches remains unclear.

Increased susceptibility to severe chronic liver damage in CXCR4 conditional knock-out mice.

Background: The chemokine SDF-1 and its receptor CXCR4 are essential for the proper functioning of multiple organs. In the liver, cholangiocytes and hepatic progenitor cells (HPCs) are the main cells that produce SDF-1, and SDF-1 is thought to be essential for HPC-stimulated liver regeneration.

Aims: In this study, CXCR4 conditionally targeted mice were used to analyze the role of SDF-1 in chronically damaged liver.

The endothelial antigen ESAM monitors hematopoietic stem cell status between quiescence and self-renewal.

Whereas most hematopoietic stem cells (HSC) are quiescent in homeostasis, they actively proliferate in response to bone marrow (BM) injury. Signals from the BM microenvironment are thought to promote entry of HSC into the cell cycle. However, it has been cumbersome to assess cycle status of viable HSC and thus explore unique features associated with division.

Bone marrow niches for hematopoietic stem cells and immune cells.

In mammals, hematopoietic stem cells (HSCs), which give rise to all blood cells and their progenies, including immune cells are controlled by special microenvironments, termed niches in the bone marrow during homeostasis and infection. However, the identity, nature and function of these niches remain unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (termed endosteal niche).

Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells.

In the bone marrow, hematopoietic stem cells (HSCs) are maintained by special microenvironments, termed niches. The nature and function of these niches, however, remains unclear. HSCs are thought be in contact with bone-lining osteoblasts, but recent studies have suggested that only a small subpopulation of HSCs reside in this endosteal niche.

Emergency evacuation! Hematopoietic niches induce cell exit in infection.

The roles of hematopoietic stem and/or progenitor cell niches during infection remain unclear. In this issue of Immunity, Shi et al. (2011) reveal that these niches upregulate MCP1 chemokine expression, inducing emigration of bone marrow monocytes into the circulation via the endothelium.

C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells.

Increasing evidence suggests that myeloid bone marrow-derived cells (BMDCs) play a critical role in lung metastasis. Blockade of VEGF receptor 1 (VEGFR1) has been proposed as a potential strategy to limit myeloid BMDC recruitment to tumors. However, preclinical evidence indicates that this strategy may not be effective in all tumors.

CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice.

Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development.

The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche.

Hematopoietic stem cells (HSCs) and their lympho-hematopoietic progeny are supported by microenvironmental niches within bone marrow; however, the identity, nature, and function of these niches remain unclear. Short-term ablation of CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells in vivo did not affect the candidate niches, bone-lining osteoblasts, or endothelial cells but severely impaired the adipogenic and osteogenic differentiation potential of marrow cells and production of the cytokines SCF and CXCL12 and led to a marked reduction in cycling lymphoid and erythroid progenitors. HSCs from CAR cell-depleted mice were reduced in number and cell size, were more quiescent, and had increased expression of early myeloid selector genes, similar to the phenotype of wild-type HSCs cultured without a niche.

Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation.

Disrupted hematopoiesis and delayed immune reconstitution are life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although graft-versus-host disease (GVHD) is a major risk factor for the bone marrow (BM) insufficiency, how GVHD impairs BM hematopoiesis has been largely unknown. We hypothesized that BM stromal niche could be a target of GVHD.

The CXCL12 (SDF-1)/CXCR4 axis is essential for the development of renal vasculature.

CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1) is a unique homeostatic chemokine that signals through its cognate receptor, CXCR4. CXCL12/CXCR4 signaling is essential for the formation of blood vessels in the gastrointestinal tract during development, but its contribution to renal development remains unclear. Here, we found that CXCL12-secreting stromal cells surround CXCR4-positive epithelial components of early nephrons and blood vessels in the embryonic kidney.

Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling.

Plasmacytoid dendritic cells (pDCs), also known as type I interferon (IFN)-producingcells, are thought to play central roles in antiviral immunity and the pathogenesis of some autoimmune diseases. pDCs are produced from hematopoietic stem cells in bone marrow. However, the environmental regulation of the development of pDCs is not fully understood.

Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches.

In the bone marrow, the special microenvironment niches nurture a pool of hematopoietic stem cells (HSCs). Many HSCs reside near the vasculature, but the molecular regulatory mechanism of niches for HSC maintenance remains unclear. Here we showed that the induced deletion of CXCR4, a receptor for CXC chemokine ligand (CXCL) 12 in adult mice, resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury, although it did not impair expansion of the more mature progenitors.

Cellular niches controlling B lymphocyte behavior within bone marrow during development.

In bone marrow, hematopoiesis is thought to depend on special microenvironments known as niches that maintain blood cells. However, the identity of niches and interaction of blood cells with niches remain poorly understood. Here we identify stage-specific cellular niches for B lymphopoiesis.

Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny.

The physiological role of SDF-1 on hematopoietic stem cells (HSCs) remains elusive. We show that colonization of bone marrow by HSCs in addition to myeloid cells is severely impaired in SDF-1(-/-) embryos by a long-term repopulation assay. Colonization of spleen by HSCs was also affected, but to a lesser extent.