Decreased Circulating Progenitor Cell Number and Failed Mechanisms of Stromal Cell-Derived Factor-1α Mediated Bone Marrow Mobilization Impair Diabetic Tissue Repair

OBJECTIVE-Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing. RESEARCH DESIGN AND METHODS-Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Lepr(db/db)) mice. Blood and bone marrow PCs were collected at multiple time points. RESULTS-Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin(-)/sca-1(+)/ckit(+) in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 +/- 3.2% lin(-)/ckit(+)/sca1(+) vs. 13.5 +/- 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1 alpha (SDF-1 alpha) expression (40% reduction, P < 0 01) In contrast, a failed switch mechanism in diabetic bone marrow SDF-1 alpha expression (2.8% reduction) resulted in impaired PC mobilization Restoring the bone marrow SDF-1 alpha switch (54% reduction, P < 0 01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6 8 +/- 2 0-fold increase in lin(-)/ckit(-), P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 +/- 5 0% vs 11 9 +/- 3% at day 7, P > 0 05, 73.0 +/- 6.4% vs. 36 5 +/- 7% at day 14, P < 0 05, and 88.0 +/- 5.7% vs 66.7 +/- 5% at day 21, P > 0 05, respectively) CONCLUSIONS-Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1 alpha levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischenuamediated pathology associated with diabetes by reducing bone marrow SDF-1 alpha, restoring normal PC mobilization and tissue healing. Diabetes 59:1974-1983, 2010