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Review
. 2012 Jan;26(1):34-53.
doi: 10.1038/leu.2011.197. Epub 2011 Sep 2.

Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4

M P Rettig  1 , G Ansstas, J F DiPersio
Affiliations
Review

Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4

M P Rettig et al. Leukemia. 2012 Jan.

Abstract

Successful hematopoietic stem cell transplant requires the infusion of a sufficient number of hematopoietic stem/progenitor cells (HSPCs) that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely manner. Stem cells harvested from peripheral blood are the most commonly used graft source in HSCT. Although granulocyte colony-stimulating factor (G-CSF) is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients. Both the chemokine receptor CXCR4 and the integrin α(4)β(1) (very late antigen 4 (VLA-4)) have important roles in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of CXCR4 or VLA-4 with their ligands results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF. In this review, we discuss the development of small-molecule CXCR4 and VLA-4 inhibitors and how they may improve the utility and convenience of peripheral blood stem cell transplantation.

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Conflict of interest statement

Conflict-of-interest disclosure

M.P.R. and J.F.D have received honoraria from Genzyme Corp.

Figures

Figure 1
Figure 1. Models of HSPC mobilization by G-CSF and inhibitors of CXCR4 and VLA-4
(A) Bone marrow environment at baseline. HSPCs in the endosteal niche are likely in close contact with osteoblasts and nestin+ mesenchymal stem cells (MSCs), both of which express numerous HSPC retention factors, including CXCL12, VCAM-1 and SCF. The perivascular niche is more distant from the endosteum and includes both nestin+ MSCs and CXCL12 abundant reticular cells. Cells of the monocytic lineage support the maintenance of osteoblasts and MSCs. β-adrenergic nerve cells of the sympathetic nervous system regulate MSC proliferation and induce circadian oscillations of CXCL12 expression. (B) Model of G-CSF-induced HSPC mobilization. Cells of the monocytic lineage express the receptor for G-CSF and provide factors that support the survival of MSCs and osteoblasts. Upon 4 to 5 days of stimulation with G-CSF, the monocytes/macrophages disappear, leading to the loss of osteoblast lineage cells and reduced expression of CXCL12, VCAM-1, and SCF on MSCs. Reduced expression of these key HSPC retention factors is also observed following G-CSF signaling through β-adrenergic nerve cells. The net effect of these signaling cascades is the disruption of HSPC retention interactions and mobilization of HSPCs into the peripheral blood. (C–D) Model of HSPC mobilization by inhibitors of CXCR4 or VLA-4. Targeted disruption of the interaction of CXCR4 or VLA-4 with their ligands results in the rapid (within hours) and reversible mobilization of HSPCs into the peripheral circulation. An additive or synergistic affect on HSPC mobilization is observed when a CXCR4 inhibitor is combined with a VLA-4 antagonist, G-CSF or their combination. When used alone, inhibitors of CXCR4 and VLA-4 mobilize fewer HSPCs than G-CSF.
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