New York University School of Medicine, New York, New York, USA.
Diabetes. 2010 Aug;59(8):1974-83. doi: 10.2337/db09-0185. Epub 2010 May 18.
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.
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.
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-1alpha (SDF-1alpha) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1alpha expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1alpha 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).
Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1alpha levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemia-mediated pathology associated with diabetes by reducing bone marrow SDF-1alpha, restoring normal PC mobilization and tissue healing.
祖细胞（PCs）有助于出生后血管新生和组织修复。在此，我们探索了导致糖尿病患者循环 PC 数量减少的机制，并提出了一种恢复循环 PC 数量、外周血管新生和组织愈合的新治疗方法。
在野生型（C57BL/J6）和糖尿病（Lepr(db/db)）小鼠上创建皮肤伤口。在多个时间点采集血液和骨髓 PC。
糖尿病动物的伤口愈合明显延迟与循环 PC 数量减少有关（lin(-)/sca-1(+)/ckit(+)的倍数增加，野生型为 7.6 倍；而糖尿病为 1.9 倍；P<0.01），尽管基线时骨髓中的 PC 数量充足（lin(-)/ckit(+)/sca1(+)的百分比为 14.4 +/- 3.2%；而野生型为 13.5 +/- 2.8%）。外周创伤后正常的骨髓 PC 动员是由于骨髓基质细胞衍生因子-1alpha（SDF-1alpha）表达的必要转换（减少 40%，P<0.01）。相比之下，糖尿病骨髓 SDF-1alpha 表达的转换机制失败（减少 2.8%）导致 PC 动员受损。用plerixafor（Mozobil，前称为 AMD3100）降低骨髓 SDF-1alpha 转换（减少 54%，P<0.01）可增加循环中糖尿病患者的 PC 数量（lin(-)/ckit(+)的倍数增加 6.8 +/- 2.0 倍；P<0.05），并显著改善糖尿病伤口愈合情况，与假处理对照组相比（第 7 天为 32.9 +/- 5.0%；而第 14 天为 11.9 +/- 3%；P>0.05；第 14 天为 73.0 +/- 6.4%；而第 21 天为 36.5 +/- 7%；P<0.05；第 21 天为 88.0 +/- 5.7%；而第 66.7 +/- 5%；P>0.05）。
成功的缺血诱导骨髓 PC 动员是由骨髓 SDF-1alpha 水平的转换介导的。在糖尿病中，这种转换失败。plerixafor 通过降低骨髓 SDF-1alpha、恢复正常的 PC 动员和组织愈合，代表了一种改善与糖尿病相关的缺血性病理的潜在治疗药物。
