Microenvironmental influences on human B‐cell development

Abstract

Mammalian B-cell development can be viewed as a developmental performance with several acts. The acts are represented by checkpoints centered around commitment to the B-lineage and functional Ig gene rearrangement--culminating in expression of the pre-B-cell receptor (pre-BCR) and the BCR. Progression of cells through these checkpoints is profoundly influenced by the fetal liver and adult bone marrow (BM) stromal cell microenvironments. Our laboratory has developed a model of human B-cell development that utilizes freshly isolated/non-transformed human BM stromal cells as an in vitro microenvironment. Human CD34+ hematopoietic stem cells plated in this human BM stromal cell microenvironment commit to the B lineage and progress through the pre-BCR and BCR checkpoints. This human BM stromal cell microenvironment also provides survival signals that prevent apoptosis in human B-lineage cells. Human B-lineage cells exhibit differential expression of Notch receptors and human BM stromal cells express the Notch ligand Jagged-1. These results suggest a potential role for Notch in regulating B-lineage commitment and/or progression through the pre-BCR and BCR checkpoints.

Immunoregulatory function of mesenchymal stem cells

“…The supportive interaction of mesenchymal stromal cells with hematopoietic progenitors in the BM is well exemplified by the fundamental influence of the former cells on early B cell lymphopoiesis. In this context, it has been shown that the close interaction with BM stromal cells is crucial for the normal development of progenitor B cells and is supported by cytokines including interleukin-7 (IL-7), stem cell factor (SCF), Flt3 ligand, thymic stromal lymphopoietin (TSL) and CXCL12 (also known as stromal cell-derived factor-1, SDF-1) [20]. Responsiveness of B cell progenitors to cytokines requires the surface expression of the pre-B cell receptor (pre-BCR) [21] which is indispensable for pre-B cell survival, proliferation, differentiation and allelic exclusion.…”

B-chronic lymphocytic leukemia chemoresistance involves innate and acquired leukemic side population cells

“…Here, the specific phenotype of B-CLL SP cells, which was formally validated by ABCG2 and BMI-1 expressions, 20,27 was nevertheless quite incomplete as lacking typical cell surface markers of immaturity (for example, CD34, CD127). 28 However, B-CLL is a malignant disease of phenotypically mature B cells, in which clonal progeny naturally lacks expression of immaturity antigens. 25 Likewise, SP cells from other mature B-cell malignant hemopathies, such as multiple myeloma, also present phenotypes inherent to the differentiation status of their non-malignant counterpart.…”

The Onecut Transcription Factor Hepatocyte Nuclear Factor-6 Controls B Lymphopoiesis in Fetal Liver

“…Bone marrow cells were obtained by flushing two femora and two tibiae with PBS. Erythrocytes were lysed with a 0.15 M NH 4 Cl, 10 mM KHCO 3 , 0.1 mM Na 2 EDTA, pH 7.2-7.4 solution (spleen, bone marrow, and e16.5 fetal liver) or were eliminated by centrifugation in Ficoll (e17.5 and e18.5 fetal liver). Cells were filtered through a nylon membrane (80-m pores) and counted.…”

“…The second program occurs in nonhemopoietic cells, which establish with the lymphoid precursors a cross-talk that is essential for lymphopoiesis (3). Although a number of proteins that are secreted or involved in cell-cell contact to regulate B lymphopoiesis have been described (4), their regulation is poorly understood. The identification of transcription factors that control this second gene program is therefore an important step forward.…”