Mesenchymal lineage cells and their importance in B lymphocyte niches

Abstract

Early B lymphopoiesis occurs in the bone marrow and is reliant on interactions with numerous cell types in the bone marrow microenvironment, particularly those of the mesenchymal lineage. Each cellular niche that supports the distinct stages of B lymphopoiesis is unique. Different cell types and signaling molecules are important for the progressive stages of B lymphocyte differentiation. Cells expressing CXCL12 and IL-7 have long been recognized as having essential roles in facilitating progression through stages of B lymphopoiesis. Recently, a number of other factors that extrinsically mediate B lymphopoiesis (positively or negatively) have been identified. In addition, the use of transgenic mouse models to delete specific genes in mesenchymal lineage cells has further contributed to our understanding of how B lymphopoiesis is regulated in the bone marrow. This review will cover the current understanding of B lymphocyte niches in the bone marrow and key extrinsic molecules and signaling pathways involved in these niches, with a focus on how mesenchymal lineage cells regulate B lymphopoiesis.

Keywords: B lymphocytes; B lymphopoiesis; Mesenchymal cells; Osteoblasts; Osteoclasts.

Figure 1:. Simplified schematic of B lymphopoiesis

Hematopoiesis arises in the bone marrow from hematopoietic stem cells (HSCs). In the lymphoid lineage, HSCs give rise to common lymphoid progenitors (CLPs) which form T lymphocytes, B lymphocytes and natural killer cells. Expression of Ly6D on CLPs commits the CLP to the B-cell-biased lymphoid progenitor (BLP). B lymphocytes continue developing in the bone marrow through pre-pro-B, pro-B and pre-B lymphocyte stages, immature B lymphocytes then exit the bone marrow and mature in the spleen. End stage plasma cells can return to the bone marrow.

Figure 2:. The bone marrow is the site of early B lymphopoiesis

Early B lymphopoiesis occurs in the bone marrow. Hematopoietic stem cells (HSCs) differentiate to common lymphoid progenitors (CLPs) and B lymphoid-biased progenitors (BLPs) and then become the earliest committed B cell precursor, the pre-pro-B cell. Pre-pro B cells localize next to CXCL12-abundant reticular (CAR) cells, then as they differentiate into pro-B cells they localize adjacent to IL-7-expressing stromal cells. Pre-B cells localize near Galectin-1-expressing cells within the bone marrow. Immature B cells migrate from the bone marrow to mature at the spleen. End stage plasma cells then return to the bone marrow. Osteoblast lineage cells are known to play essential roles in regulating B lymphopoiesis; perivascular mesenchymal stem cells (MSCs) differentiate into osteoblast progenitors (OPs) and both these cell types express factors that regulate B lymphopoiesis. B lymphocytes can in turn regulate bone by altering osteoclastogenesis via production of RANKL, which binds to RANK on the surface of osteoclast precursors. Mature B lymphocytes have also been shown to be a major source of OPG, thereby inhibiting osteoclastogenesis (not shown).

Figure 3:. Identifiers of B lymphocyte subsets and extrinsic regulators of B lymphopoiesis

Expression of cell surface antigens allows for identification of B lymphocyte subsets in the bone marrow. The purple panel indicates expression of B220, IgM, CD19, CD43, CD24 (HSA), BP-1 (6C3) and IgD through differentiation from pre-pro-B lymphocytes to immature B lymphocytes and in recirculating mature B lymphocytes plus the corresponding fraction [93]. Expression as determined by flow cytometry is indicated as positive (+), positive-bright (++) or negative (−). The green panel indicates positive (+) and negative (−) expression of receptors and adhesion molecules involved in B lymphopoiesis. The blue panel indicates extrinsic factors expressed by stromal cells in the microenvironment that are important in the development of early B cell precursors and the specific stages they regulate in the bone marrow and are discussed in this review. Extrinsically produced factors can either positively (+ to ++) or negatively (−) regulate each stage of B lymphopoiesis as indicated. *cKIT (CD117) is upregulated on malignant plasma cells in some multiple myeloma patients [104].