Elsevier

Bone

Volume 119, February 2019, Pages 42-56
Bone

Review Article
Mesenchymal lineage cells and their importance in B lymphocyte niches

https://doi.org/10.1016/j.bone.2017.11.018Get rights and content

Highlights

  • A thorough overview of the role of mesenchymal lineage cells in regulating B lymphopoiesis

  • Summaries of mesenchymal cell conditional knockouts and resulting B cell defects

  • Key mesenchymal cell-derived regulators of B lymphocytes are highlighted

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.

Introduction

Bone is a dynamic organ that is constantly being broken down and replenished in a process known as bone remodeling. Bone remodeling is carried out by two cell types on the bone surface; osteoclasts which remove bone via resorption and osteoblasts that subsequently replace bone by forming a new bone matrix [1]. Bone remodeling is influenced by many cell types within the bone marrow, most obviously including mature osteoblasts and osteoclasts, but also other cell types including matrix-embedded osteocytes, osteoblast progenitors, osteoclast precursors, macrophages, T lymphocytes [1], [2] and B lymphocytes [3]. A large focus in bone biology is the coupling of osteoblasts and osteoclasts in regulating bone formation. However, osteoblasts have also been shown to be key regulators of other hematopoietic cells. Of interest in this review is the contribution of mesenchymal lineage cells, including osteoblasts, to the regulation of B lymphopoiesis in mice.

Section snippets

B lymphopoiesis

B lymphocytes, commonly called B cells, are antibody-producing white blood cells that primarily function as a part of the adaptive immune system. B lymphopoiesis is the process of mature B lymphocyte formation, which in sequential stages take part in the bone marrow and spleen in adult mice. The tightly regulated process of B lymphopoiesis is reliant on intrinsic and extrinsic stimuli, the latter predominantly being produced by non-hematopoietic microenvironmental cells.

There are multiple

Microenvironment regulation of hematopoiesis

Over the last two decades there has been increasing interest in the role of cells within hematopoietic microenvironments (also known as niches) in nurturing healthy [17], [18], [19], [20], [21] and malignant [22], [23], [24], [25] hematopoiesis and bone remodeling [1], [2]. ‘Microenvironments’ or ‘niches’ are compartments that function to regulate the numbers and types of hematopoietic cells that are developing in the microenvironment by influencing their development into distinct hematopoietic

The mesenchymal niches for B lymphopoiesis

Mesenchymal cells, including osteoblast lineage cells, are crucial regulators of the B lymphocyte lineage, influencing both commitment to the B lymphocyte lineage and the progression of the immature B cells through the early stages of B lymphopoiesis. The importance of osteoblast lineage cells in B lymphopoiesis has been made apparent by their ability to support all stages of differentiation from HSCs to immature B cells in vitro, and the impaired formation of B lymphocyte precursors when

Extrinsic factors regulating B lymphopoiesis

Chemokines, adhesion molecules and various cytokines expressed by stromal cells in the microenvironment are essential for the regulation of early B lymphopoiesis as either positive or negative regulators. These factors are known to govern specific stages of B lymphocyte development and must be delivered to the appropriate B cell precursor at the appropriate stage of development to enable healthy B cell maturation. While it is recognized that these factors are essential for the development of B

PTH

Signaling through the parathyroid hormone (PTH) receptor (PTH1R) in bone is crucial for skeletal development and mineral homeostasis, and intermittent activation of PTH1R with either recombinant PTH [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34] (teriparatide) or modified recombinant PTH-related peptide (PTHrP [1], [2], [3], [4], [5], [6], [7], [8],

B lymphocyte regulation of osteoclastogenesis

This review has focused on the importance of bone and osteoblast-lineage cells in supporting B lymphopoiesis, yet it is also interesting to note that B lymphocytes are capable of influencing bone mass. B lymphocytes express both RANKL [3] and its decoy receptor OPG [180] [181], meaning that they can regulate osteoclastogenesis (and, in turn, influence the regulation of osteoblasts). B cells at different stages of development, in particular mature B lymphocytes and plasma cells, have been shown

Osteoblasts and multiple myeloma

Multiple myeloma is a malignancy of differentiate B cells (plasma cells) in the bone marrow that causes a destructive bone disease in up to 90% of patients [186]. Many patients with myeloma bone disease experience bone pain, hypercalcemia and pathological fractures severely reducing quality of life [187], and the bone disease increases the risk of death by 20% [188]. The bone disease is instigated by the release of factors that directly lead to an increased number and activity of osteoclasts

Conclusions

Over the past two decades, the importance for the bone marrow microenvironment in facilitating healthy development of B cells has become increasingly evident. The composition of B lymphocyte niches is now known to change throughout B lymphopoiesis and has been at least partially defined, with CAR cells, IL-7-expressing cells and GAL1-expressing cells playing unique roles. Despite this, there is still a lot of confusion surrounding how much these populations overlap and what makes them distinct

Acknowledgements

This review was supported in part by grants from the National Health and Medical Research Council of Australia (APP1127551) (to LEP), NIH grant DP2 OD008466 (to JYW), Bloodwise Programme Grant (ADC) and the Victorian State Government Operational Infrastructure Support Program (to St. Vincent's Institute).

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