The chemokine SDF‐1, stromal cell‐derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4

Abstract

In the bone marrow, progenitor (pro-) and precursor (pre-) B cells depend on close contact with stromal cells for growth and maturation. Stromal cell-derived factor 1 (SDF-1), also known as pre-B cell growth-stimulating factor, is produced by bone marrow stromal cells and was reported to act together with interleukin-7 as co-mitogen for pre-B cells. SDF-1 was recently shown to be a chemokine which is chemotactic for different types of leukocytes and acts via the chemokine receptor CXCR4. Using sorted B220+ bone marrow cells and several B cell lines characteristic for different stages of B lymphopoiesis, we now show that SDF-1 is a potent attractant for pro- and pre-B cells, but is inactive on B cells at later stages of development. In early B cell precursors, SDF-1 induced intracellular Ca2+ mobilization and in vitro migration with a potency and efficacy similar to that observed for chemokines acting on blood leukocytes. These responses were mediated via CXCR4 as they could be inhibited by an antireceptor antibody. SDF-1 is the first chemokine shown to act on early-stage B cell precursors. Mice lacking SDF-1 die perinatally and show a severe deficiency in B lymphopoiesis. We propose that SDF-1 released from the stromal cells exerts its critical hematopoietic function by selectively attracting and confining early B cell precursors within the bone marrow microenvironment that provides the necessary factors for growth and differentiation.

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

“…B-lymphocyte progenitor cells express the CXCR4 receptor at high levels. 48,49 Mice deficient in SDF-1 have severely reduced B-lymphocyte progenitors in the marrow, 50,51 and studies have demonstrated that SDF-1 supports the homing 40,48,49 and proliferation 52 of marrow B-lymphocyte progenitors. Furthermore, reduced marrow IL-6 mRNA expression in Prg4 mutant mice may contribute to decreased frequency of B-lymphocytic cells, because IL-6 supports physiological B-lymphopoiesis.…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…47,93,94 Furthermore, anti-human CXCR4 or CXCL12 antibodies also significantly impair metastasis and progression of non-Hodgkin's lymphoma, breast, lung and prostate tumors in animal models. [95][96][97][98] The unique properties of monoclonal antibody (mAb) therapies, including their high affinity and specificity, and the differential expression of target antigen in tumor cells versus normal cells make them attractive agents for cancer immunotherapy.…”

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes

“…In later stages of bone marrow differentia-tion lymphocytes respond to SLC/ELC, BLC and LARC [27]. It will be interesting to see whether the retained CXCR4 will regain access to the signaling pathways that allow cells emigrating from the lymph node to be attracted to and/or retained in the bone marrow [9,38,47,48]. Preliminary results indicate that emigrating plasmablasts express the activated form of § 4 g 1 integrin which might allow chemokine-independent immigration to target tissues via vascular cell adhesion molecule (VCAM)-1 (Finke et al, submitted).…”