Murine Bone Marrow Niches from Hematopoietic Stem Cells to B Cells

Abstract

After birth, the development of hematopoietic cells occurs in the bone marrow. Hematopoietic differentiation is finely tuned by cell-intrinsic mechanisms and lineage-specific transcription factors. However, it is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic stem cells (HSC) and their differentiation into more mature lineages. Mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish a direct contact with developing hematopoietic cells. A number of recent studies have addressed in mouse models the specific molecular events that are involved in the cellular crosstalk between hematopoietic subsets and their niches. This has led to the concept that hematopoietic differentiation and commitment towards a given hematopoietic pathway is a dynamic process controlled at least partially by the bone marrow microenvironment. In this review, we discuss the evolving view of murine hematopoietic⁻stromal cell crosstalk that is involved in HSC maintenance and commitment towards B cell differentiation.

Keywords: B lymphopoiesis; bone marrow niches; early hematopoiesis; stromal cells.

Figure 1

Murine early hematopoiesis from long-term hematopoietic stem cells towards the different lineages. Plain and dashed arrows show the main and the alternative branch points, respectively. Hematopoietic progenitors do not express markers of the different hematopoietic lineages and are therefore said to be lineage-negative (Lin⁻). Markers used to characterize the different hematopoietic progenitors are indicated. LT-HSC: long-term hematopoietic stem cell (HSC); ST-HSC: short-term HSC; MPP: multipotent progenitor; LMPP: lymphoid-biased multipotent progenitor; MEP: megakaryocyte-erythroid progenitor; GMP: granulocyte-monocyte progenitor; CLP: common lymphoid progenitor; Mega: megakaryocyte; Erythro: erythrocyte; Granulo: granulocyte; Mono: monocyte; Lympho: lymphocyte; Lin: lineage markers.

Figure 2

Murine bone marrow (BM) B cell differentiation. (A) Schematic representation of the different B cell differentiation stages with their denomination according to the Basel and Philadelphia nomenclatures. The pattern of expression of the main markers used to characterize each subset is shown with a line. The thickness of the line is representative of the level of expression. The dotted lines indicate subsets where expression is progressively lost. VDJ_H and VJ_L rearrangements are indicated; (B) BM B lymphopoiesis analysis by flow cytometry according to the Basel nomenclature; (C) BM B lymphopoiesis analysis by flow cytometry according to the Philadelphia nomenclature. The gating strategy and the main subsets are indicated in the panels; (D) BM B lymphopoiesis analysis by flow cytometry taking into consideration both nomenclatures. This strategy improves the resolution of the subsets, particularly of the pro-B, the pre-BI and the large pre-BII fractions (Fr. B to Fr. C’). Indeed, while the separation between pro-B and pre-BI cells (Fr. B and C) is not possible with the Basel nomenclature and the distinction between pre-BI and large pre-BII (Fr. C and C’) with CD24 is dependent on mouse strains, the simultaneous use of BP1 and CD25 allows a clear definition of the three subsets.

Figure 3

Bone marrow niches for hematopoietic stem cells and B cells. HSC are located in both endosteal/arteriolar and in peri-sinusoidal regions which express high levels of CXCL12 and stem cell factor (SCF). Quiescent HSC are enriched in the endosteal/arteriolar niche. Differentiation of MPP up to the pro-B cell stage takes place in the peri-sinusoidal niche, where the level of CXCL12 and IL7 are high. Pre-B cell then relocalize close to GAL1-expressing stromal cells located away from the sinusoids. At the next immature B cell stage, cells expressing an auto-reactive B cell receptor (BCR) are retained in the BM in order to initiate receptor editing, while non-autoreactive cells leave the BM to finish their maturation in the periphery. Mature/recirculating B cells and plasma cells follow CXCL12 gradients to home to the BM. Recirculating B cell survival relies on dendritic cells. PC survival relies on the secretion of IL6 and A proliferation-inducing ligand (APRIL) by monocytes, eosinophil, and megakaryocytes. The colored triangle represents the gradient of IL7 expression from high (red) to low (green). The table in the bottom right summarizes the influence of CXCL12 and SCF specific deletion in PSS cells, pericytes, or BMEC on HSC retention (R) and maintenance (M). MPP; multipotent progenitor; CLP: common lymphoid progenitor; BLP: B lymphoid progenitor; Imm. B: immature B cell; Recirc. B: recirculating B cell; PC: plasma cell; Mono: monocyte; Eosino: eosinophil; Mega: megakaryocyte; DC: dendritic cell; aBMEC: arteriolar bone marrow endothelial cell; sBMEC: sinusoidal BMEC; PSS cell: peri-sinusoidal stromal cell.