Modulation of the SDF-1-CXCR4 axis by the third complement component (C3)--implications for trafficking of CXCR4+ stem cells

Several organs including hematopoietic ones may regenerate by attracting stem cells that are mobilized from their niches in response to stress related to tissue/organ damage and after mobilization circulate in the peripheral blood. The trafficking of these cells is regulated by alpha-chemokine stromal derived factor-1 (SDF-1) that is upregulated in damaged organs and binds to seven-transmembrane-span G-protein-coupled CXCR4 receptor that is expressed on circulating stem cells. In parallel, evidence has accumulated that the complement (C) system, which is part of innate immunity, may also orchestrate regeneration. C becomes activated with the release of the third complement component (C3) cleavage fragments (e.g., C3a, desArgC3a, and iC3b) during tissue/organ injury. Our recent work demonstrated that these fragments modulate responsiveness of CXCR4+ stem cells to an SDF-1 gradient. Thus the high concentration of both SDF-1 and C3 cleavage fragments in damaged organs results in the formation of an optimal gradient for chemoattracting circulating CXCR4+ stem cells. In this review we will focus on interactions between the SDF-1-CXCR4 axis and the C3 cleavage fragments in a model of mobilization, trafficking, and homing of hematopoietic stem/progenitor cells (HSPC).