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E. Deindl and C. Kupatt (eds.), Therapeutic Neovascularization — Quo Vadis?, 215-225. © 2007 Springer.

of hematopoietic stem cells. This was elegantly documented by Abkowitz and colleagues who used parabiotic mice to demonstrate that hematopoietic stem cells, mobilized to the blood in response to cytokine exposure, are destined to later return to marrow [5]. There is also a large body of evidence suggesting that homing and mobilization are mirror image processes when it comes to expression patterns of adhesion molecules and chemokine receptors on hematopoietic progenitor cells [6-8]. Yet the homing process in the bone marrow is the most extensively described. One reason is the success of bone marrow transplantation by intravenous infusion. This process relies on the ability of hematopoietic stem cells to "home" or engraft in the recipient's bone marrow. This process requires a cascade of events, which includes specific molecular recognition, cell-cell adhesion, transendothelial migration, and functional repopulation of the depleted bone marrow [8]. Drugs, antibodies and peptides used to block specific cytokines and/or adhesion molecules have led to the conclusion that high levels of those are required in the bone marrow for efficient homing of circulating hematopoietic stem cells into the bone marrow niche. In the next paragraph, we will focus on some of these actors but in the opposite context of mobilization from the bone marrow.

2. STEM CELL FACTOR (sKitL) AND STROMAL-DERIVED FACTOR (SDF-1)

As mentioned above, when compared with progenitor cell homing to the bone marrow, the mobilization of hematopoietic stem cells responds to diametric cytokine/growth factor gradients. Today, these gradients are known to arise in part from the activity of proteolytic enzymes like elastase, cathepsin G and gelatinases (MMP-2 and MMP-9). The action of these proteinases allows the cleavage of adhesive bonds on stromal cells, but also the cleavage of specific mobilization actors such as the Kit ligand and SDF-1.

Activation of MMP-9 results in the cleavage of membrane-bound Kit ligand from bone marrow stromal cells, leading to the release of soluble Kit ligand (sKitL, also named stem cell factor) [9]. Consecutively, quiescent hematopoietic stem cells expressing cKit (the receptor of sKitL) are translocated to a permissive zone that is conducive to proliferation and mobilization to the circulation. The result is the disengagement of stem cells from the bone marrow and the passage in the blood stream through the sinusoidal endothelium.

Cleavage of SDF-1 at the surface of stromal cells and of its cognate receptor CXCR4 located in the membrane of hematopoietic stem cells is also thought to facilitate the mobilization process [10-13]. Combined with the production of SDF-1 by ischemic peripheral tissues and circulating platelets [14], the protease-driven degradation of bone marrow SDF-1 (and CXCR4) leads to the formation of an important SDF-1 gradient (Figure 1). In a very elegant study, Ceradini and colleagues showed that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen

Figure 1. The vasculogenic SDF-1/CXCR4 axis. The double role of SDF-1 in the mobilization of endothelial progenitor cells (EPC) from the bone marrow and in their homing in peripheral ischemic tissue is represented. In response to hypoxia, large amounts of SDF-1 are produced in ischemic tissues. Local SDF-1 impregnation decorates the endothelium of the vessels located nearby the ischemic regions; this also leads to the intravasation of the excess SDF-1. In the bone marrow, soluble SDF-1 transported by the blood stream from the periphery displaces the CXCR4 receptor binding to the membrane-bound SDF-1 (which normally maintains progenitor cells in the bone marrow niches). EPC detached from their support migrate and leave the bone marrow through the local vasculature. Once in the blood, they will distribute in preference in SDF-1-expressing tissues and in particular, will adhere on the SDF-1-coated endothelium of the vessels from the ischemic region. As emphasized in the text, other mechanisms are involved in the alteration of the CXCR4/SDF-1 interaction; they all concur to the formation of a SDF-1 gradient in favour of ischemic tissues and the consecutive detachment of CXCR4+ hematopoietic cells (see also Figure 2)

Figure 1. The vasculogenic SDF-1/CXCR4 axis. The double role of SDF-1 in the mobilization of endothelial progenitor cells (EPC) from the bone marrow and in their homing in peripheral ischemic tissue is represented. In response to hypoxia, large amounts of SDF-1 are produced in ischemic tissues. Local SDF-1 impregnation decorates the endothelium of the vessels located nearby the ischemic regions; this also leads to the intravasation of the excess SDF-1. In the bone marrow, soluble SDF-1 transported by the blood stream from the periphery displaces the CXCR4 receptor binding to the membrane-bound SDF-1 (which normally maintains progenitor cells in the bone marrow niches). EPC detached from their support migrate and leave the bone marrow through the local vasculature. Once in the blood, they will distribute in preference in SDF-1-expressing tissues and in particular, will adhere on the SDF-1-coated endothelium of the vessels from the ischemic region. As emphasized in the text, other mechanisms are involved in the alteration of the CXCR4/SDF-1 interaction; they all concur to the formation of a SDF-1 gradient in favour of ischemic tissues and the consecutive detachment of CXCR4+ hematopoietic cells (see also Figure 2)

tension [15]. HIF-1-induced SDF-1 expression in turn increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue (Figure 1). Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Interestingly, this study led to the observation that the bone marrow compartment is also characterized by discrete regions of hypoxia that account for the local SDF-1 expression and progenitor cell tropism [15].

SDF-1-induced stem cell mobilization is thought to rely on MMP-9. SDF-1-mediated mobilization and incorporation of hematopoiteic stem cells into ischemic limbs are, for instance, impaired in MMP9-/- mice but restored by the transplantation of CXCR4+ progenitor cells [16]. Also, sKitL and thrombopoietin induce the release of SDF-1 from platelets in response to a large variety of cytokines [16]. Peripheral hypoxic gradients and sKitL stimulation therefore lead to high levels of circulating SDF-1 which, together with the local degradation of CXCR4 and SDF-1 in the bone marrow (see above), reverse the physiological (bone marrow-favorable) SDF-1 gradient. Consecutively, CXCR4+ progenitor cells are forced to exit the bone marrow to be recruited to regenerating tissues.

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