Key Points
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The bone marrow occupies the medullary cavities of bones throughout the skeleton, and B-cell development occurs within a complex microenvironment in the bone marrow.
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B-cell precursors are divided into four populations termed fraction A (pre-pro-B cells), fraction B (pro-B cells), fraction C (pro-B cells) and fraction D (pre-B cells), and the differentiation pathway is thought to proceed from fractions A to B to C to D.
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Cells in the pre-pro-B-cell fraction have the potential to give rise to the T-cell, natural killer-cell and dendritic-cell lineages as well as the B-cell lineage. Intermediate precursor cells, between haematopoietic stem cells (HSCs) and the earliest B-cell precursors, including lymphoid-primed multipotential progenitors, which lack erythro-megakaryocytic differentiation potential but retain myeloid-cell, B-cell and T-cell differentiation potential, and common lymphoid progenitors (CLPs), which can generate B cells and T cells but not myeloid-lineage cells, have been identified.
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The development of B-cell precursors requires environmental factors that are probably secreted in bone-marrow niches. CXC-chemokine ligand 12 (CXCL12) is essential for the generation of pre-pro-B and pro-B cells, and for the homing of plasma cells to the bone marrow. FLT3 (fms-related tyrosine kinase 3) ligand is essential for the generation of CLPs and pre-pro-B cells. Interleukin-7 (IL-7) is essential for generation of pro-B and pre-B cells but not CLPs or pre-pro-B cells. However, it is required for B-cell differentiation potential of CLPs and pre-pro-B cells. Stem-cell factor plays an essential role in B-cell development from pro-B cells in adults. RANK (receptor activator of nuclear factor-κB) ligand is involved in the generation of pre-B cells and immature B cells.
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All known requisite factors for B-cell development are thought to be produced by the cells that are located in the bone marrow. Primary osteoblasts produce factors that support early B-cell lymphopoiesis in in vitro culture. In addition, there is a small population of reticular cells that express high levels of CXCL12 (CXCL12hi reticular cells), and a distinct subset of fibroblast-like cells that bind IL-7-specific antibody and are located away from the osteoblasts and CXCL12hi reticular cells. CXCL12hi reticular cells and IL-7-expressing cells might be cellular niches for B-cell development.
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Multipotential haematopoietic cells are located near the osteoblasts, endothelial cells or CXCL12hi reticular cells. Pre-pro-B cells are in contact with CXCL12hi reticular cells, whereas pro-B cells move away and instead adjoin the IL-7-expressing cells. Subsequently, pre-B cells leave IL-7-expressing cells. End-stage B cells (plasma cells) again associate with CXCL12hi reticular cells.
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It will be important to know what cell populations are the main intermediates between HSCs and early B-cell precursors and to identify their cellular niches. Studies of cellular niches would provide insight into the nature of spatiotemporal regulation of B-cell development in vivo.
Abstract
B-cell development is known to occur in a complex bone-marrow microenvironment but its functional organization remains unclear. It is thought that bone-marrow stromal cells create distinct microenvironments, known as niches, that provide support for haematopoiesis and B-cell development. Although it has been more than 20 years since the development of a culture system that allows the growth of B-cell progenitors on bone-marrow-derived stromal cells in vitro, it is only recently that studies have provided a novel basis for understanding the nature of the niches for B-cell development in vivo. This article summarizes the recent advances in research on the earliest B-cell precursors, their requisite environmental factors and the cellular niches that supply these factors and maintain B cells during their development.
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Acknowledgements
We thank K. Tokoyoda and T. Egawa for their contribution to the work cited, and M. Sato, H. Yoshida and S. Sakaguchi for their help in preparation of this paper and discussions. Our studies were funded by grants from the Ministry of Education, Science, Sports and Culture of Japan, and the Uehara Memorial Foundation.
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Glossary
- Medullary cavities
-
In typical long bones, such as the femur or the humerus, the shaft consists of a thick-walled, hollow cylinder of compact bone with a large central-marrow cavity. This cavity is occupied by bone marrow and is called the medullary cavity.
- Medullary vascular sinuses
-
Thin-walled vessels, the endothelium of which allows the passage of large numbers of blood cells. The arterioles in bone marrow continue into the endosteum as typical capillaries that are confluent with medullary vascular sinuses.
- Stromal cell
-
A general term for a large adherent cell. Stromal cells in the bone marrow include reticular cells, endothelial cells and macrophages.
- Endosteum
-
A thin layer of cells that have osteogenic properties and line the medullary cavity.
- Ikaros
-
A haematopoietic-cell-specific member of a family of zinc-finger transcription factors. It is an integral component of a complex containing chromatin remodelling and modifying activities. Ikaros-deficient mice lack all B cells, natural killer cells and fetal T cells, and they have severely reduced numbers of T cells and dendritic cells after birth, indicating that Ikaros is essential for development of lymphoid-lineage cells.
- Transfilter migration assay
-
An assay that allows the in vitro quantification of activities of soluble factors in inducing cell transmigration. It involves a chamber separated by a microporous polycarbonate or nitrocellulose membrane, with the lower compartment for the soluble factor and the upper compartment for the cells. After several hours, the cells harvested from the lower chamber are counted.
- SI/SI mice
-
Mice homozygous for a spontaneous null mutation at the steel (SI) locus located on chromosome 10 die around the first week of life, with many defects including severe anaemia, lack of hair pigmentation, sterility and defective intestinal-pacemaker function. They have deficiencies in melanoblasts, primordial germ cells and haematopoietic cells, including multipotential progenitors, erythrocytes and mast cells.
- W/W mice
-
Mice homozygous for a spontaneous null mutation at the dominant white spotting (W) locus located on chromosome 5 die around the first week of life, with the same symptoms as SI/SI mice.
- Vickid mice
-
(Viable c-KIT-deficient mice). Vickid mice are white, black-eyed, apparently healthy KIT-deficient mice that arose from a cross between W/+ and W/+ heterozygous mice. The molecular basis for the survival of these mice is unknown.
- Wepo mice
-
(W mutant mice rescued by erythropoietin). Wepo mice were generated by crosses between erythropoietin-transgenic W/+ mice and W/+ mice. Transgenic expression of erythropoietin is thought to boost erythropoiesis even in the absence of KIT, and rescue the W/W mice.
- Osteoclasts
-
Multinucleated cells that resorb bone. They are specialized monocyte/macrophage family members that arise from haematopoietic stem cells. Morphogenesis and remodelling of bone is controlled by processes that include the synthesis of bone by osteoblasts and the coordinate resorption of bone by osteoclasts.
- Reticular cells
-
The main stromal cells in the bone marrow, with dendritic-cell (DC)-like morphology. Unlike DCs, they have broad, sheet-like cytoplasmic processes.
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Nagasawa, T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 6, 107–116 (2006). https://doi.org/10.1038/nri1780
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DOI: https://doi.org/10.1038/nri1780
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miR-582 negatively regulates pre-B cell proliferation and survival through targeting Hif1α and Rictor
Cell Death & Disease (2022)
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The dynamic functions of IRF4 in B cell malignancies
Clinical and Experimental Medicine (2022)
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Arterial endothelium creates a permissive niche for expansion of human cord blood hematopoietic stem and progenitor cells
Stem Cell Research & Therapy (2020)