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. Most HSCs were found in contact with the cells expressing high amounts of CXCL12, which we have called CXCL12-abundant reticular (CAR) cells. CAR cells surrounded sinusoidal endothelial cells or were located near the endosteum. CXCL12-CXCR4 signaling plays an essential role in maintaining the quiescent HSC pool, and CAR cells appear to be a key component of HSC niches, including both vascular and endosteal niches in adult bone marrow.
The chemokines are a large family of small, structurally related cytokines. The physiological importance of most members of this family has yet to be elucidated, although some are inducible inflammatory mediators that determine leukocyte chemotaxis. Pre-B-cell growth-stimulating factor/stromal cell-derived factor-1 (PBSF/SDF-1) is a member of the CXC group of chemokines PBSF/SDF-1 stimulates proliferation of B-cell progenitors in vitro and is constitutively expressed in bone-marrow-derived stromal cells. Here we investigate the physiological roles of PBSF/SDF-1 by generating mutant mice with a targeted disruption of the gene encoding PBSF/SDF-1. We found that mice lacking PBSF/SDF-1 died perinatally and that although the numbers of B-cell progenitors in mutant embryos were severely reduced in fetal liver and bone marrow, myeloid progenitors were reduced only in the bone marrow but not in the fetal liver, indicating that PBSF/SDF-1 is responsible for B-cell lymphopoiesis and bone-marrow myelopoiesis. In addition, the mutants had a cardiac ventricular septal defect. Hence, we have shown that the chemokine PBSF/SDF-1 has several essential functions in development.
The chemokine stromal cell-derived factor 1, SDF-1, is an important regulator of leukocyte and hematopoietic precursor migration and pre-B cell proliferation. The receptor for SDF-1, CXCR4, also functions as a coreceptor for T-tropic HIV-1 entry. We find that mice deficient for CXCR4 die perinatally and display profound defects in the hematopoietic and nervous systems. CXCR4-deficient mice have severely reduced B-lymphopoiesis, reduced myelopoiesis in fetal liver, and a virtual absence of myelopoiesis in bone marrow. However, T-lymphopoiesis is unaffected. Furthermore, the cerebellum develops abnormally with an irregular external granule cell layer, ectopically located Purkinje cells, and numerous chromophilic cell clumps of abnormally migrated granule cells within the cerebellar anlage. Identical defects are observed in mice lacking SDF-1, suggesting a monogamous relationship between CXCR4 and SDF-1. This receptor-ligand selectivity is unusual among chemokines and their receptors, as is the function in migration of nonhematopoietic cells.
Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1. Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.
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. The earliest precursors, pre-pro-B cells and end-stage B cells, plasma cells require CXC chemokine ligand (CXCL)12. CXCL12-expressing cells are a small population of stromal cells, scattered throughout bone marrow and located some distance from the cells expressing interleukin (IL)-7. Multipotent hematopoietic progenitors are attached to the processes of CXCL12-expressing cells and pre-pro-B cells adjoin their cell bodies. Maturer pro-B cells that require IL-7 have moved away and adjoin the IL-7-expressing cells. Plasma cells again seed CXCL12-expressing cells. We demonstrate the B lymphocyte characteristic location and movement between specific niches within bone marrow during development and suggest that CXCL12 maintains the cells in the 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. Thus, the niche composed of adipo-osteogenic progenitors is required for proliferation of HSCs and lymphoid and erythroid progenitors, as well as maintenance of HSCs in an undifferentiated state.
The continuing rise in atmospheric [CO2] is predicted to have diverse and dramatic effects on the productivity of agriculture, plant ecosystems and gas exchange. Stomatal pores in the epidermis provide gates for the exchange of CO2 and water between plants and the atmosphere, processes vital to plant life. Increased [CO2] has been shown to enhance anion channel activity proposed to mediate efflux of osmoregulatory anions (Cl- and malate(2-)) from guard cells during stomatal closure. However, the genes encoding anion efflux channels in plant plasma membranes remain unknown. Here we report the isolation of an Arabidopsis gene, SLAC1 (SLOW ANION CHANNEL-ASSOCIATED 1, At1g12480), which mediates CO2 sensitivity in regulation of plant gas exchange. The SLAC1 protein is a distant homologue of bacterial and fungal C4-dicarboxylate transporters, and is localized specifically to the plasma membrane of guard cells. It belongs to a protein family that in Arabidopsis consists of four structurally related members that are common in their plasma membrane localization, but show distinct tissue-specific expression patterns. The loss-of-function mutation in SLAC1 was accompanied by an over-accumulation of the osmoregulatory anions in guard cell protoplasts. Guard-cell-specific expression of SLAC1 or its family members resulted in restoration of the wild-type stomatal responses, including CO2 sensitivity, and also in the dissipation of the over-accumulated anions. These results suggest that SLAC1-family proteins have an evolutionarily conserved function that is required for the maintenance of organic/inorganic anion homeostasis on the cellular level.
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