Role of the CXCR4/CXCL12 axis in hematopoietic stem cell trafficking

During embryogenesis, CXCR4, a chemokine receptor, and its ligand, stromal cell-derived factor-1 (SDF-1/CXCL12), are critically involved in the development of the hematopoietic organs such as the liver and the bone marrow (BM), by regulating hematopoietic stem cell (HSC) homing retention, survival, and mobilization. In adult life, the CXCR4 axis serves as the key factor for retention of hematopoietic cells including HSCs in the BM. Under physiological conditions, the exit of HSC is controlled by the circadian loop and it is an infrequent event. Tissue damage or infections increase levels of chemokines such as CXCL12 or cytokines such as G-CSF in the periphery and facilitate the exit of HSC and progenitors, which can contribute to tissue repair. Reducing the levels of CXCL12 signaling within the BM can be done either by CXCR4 antagonists or by the sequential administration of G-CSF. G-CSF, which is widely used to mobilize HSC, stimulates neutrophils activation, proteases secretion, and consequently degradation of CXCR4 and CXCL12 and indirectly increase HSC motility and release from the BM. Improved and more direct agents that will increase stem cell motility combined with superior CXCR4 antagonists may even further improve stem cell collection for transplantation. In this review, we update current knowledge about the role of CXCR4/CXCL12 in stem cell retention and mobilization.