Stroma derived factor 1 (SDF-1) is a chemokine that plays important roles in developmental neurobiology, inflammation, stem cell traffic to the bone marrow, and injured organs, such as the brain, heart, liver, and kidneys. Recently, we demonstrated that renal tubular expression and plasma levels of SDF-1 are markedly up-regulated following induction of acute ischemia/reperfusion kidney injury (AKI) in mice, and this increase in SDF-1 specifically boosted the homing of CD34 and SDF-1 receptor CXCR4 coexpressing bone marrow stem cells to the kidney (Kidney Int 2005;67:1772-8). Furthermore, we demonstrated that mesenchymal stem cell (MSC) administration protects against AKI through complex paracrine mechanisms (such as anti-inflammatory, antiapoptotic, and mitogenic) (Am J Physiol 2005;289:F31-42). Here we investigated whether by inhibiting dipeptidylpeptidase IV (CD26), which inactivates SDF-1, SDF-1-mediated homing of CXCR4 expressing MSCs to the kidney with AKI is increased and renal protection and repair are further improved. To test this hypothesis, we used bone marrow-derived MSCs from Fisher 344 rats for in vitro experiments. First, using FACS, we demonstrate that about 35% of cultured MSCs express both CD26 and CXCR4 proteins on their surface. In addition, cultured MSCs express functional CD26 and can effectively inactivate SDF-1. Finally, MSCs migration toward SDF-1 in a transwell culture system can be significantly increased by preincubation of MSCs with Diprotin A, a CD26 inhibitor, or decreased by preincubation with AMD 3100, a CXCR4 inhibitor.
Conclusion These results indicate that inhibiting CD26 augments the SDF-1-CXCR4-mediated chemotactic activity of cultured MSCs. It is therefore highly likely that pretreatment of MSCs with a CD26 inhibitor or preinfusion of such an inhibitor in vivo may augment the homing and renal protective functions of administered MSCs in experimental AKI. These promising stem cell therapeutic and organ repair strategies are currently under investigation.
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