Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1alpha mediated bone marrow mobilization impair diabetic tissue repair.
Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1alpha mediated bone marrow mobilization impair diabetic tissue repair.
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作者：
Tepper OM;Carr J;Allen RJ Jr;Chang CC;Lin CD;Tanaka R;Gupta SM;Levine JP;Saadeh PB;Warren SM
祖细胞（PC）有助于出生后的新生血管和组织修复。在这里，我们探讨了糖尿病循环PC数量减少的机制，并提出了一种新的治疗方法来恢复循环PC数量，外周新生血管和组织愈合。在野生型（C57 BL/J6）和糖尿病（Leprdb/db）小鼠上产生皮肤伤口。在多个时间点收集血液和骨髓PC。糖尿病动物的伤口闭合显著延迟与循环PC数量减少相关（野生型小鼠中lin−/sca-1+/ckit+增加1.9倍vs. 7.6倍; P < 0.01），尽管基线时骨髓中PC数量充足（14.4 ± 3.2% lin−/ckit+/sca 1 + vs. 13.5 ± 2.8%野生型）。外周创伤后，骨髓基质细胞衍生因子-1 α（SDF-1α）表达发生必要的改变（减少40%，P < 0.01）后，骨髓PC动员正常。相反，糖尿病骨髓SDF-1α表达的转换机制失败（降低2.8%）导致PC动员受损。恢复骨髓SDF-1α开关普乐沙福组（减少54%，P < 0.01）（释倍灵，以前称为AMD 3100）增加循环糖尿病PC数量（lin−/ckit+增加6.8 ± 2.0倍，P < 0.05），与假手术对照组相比，糖尿病伤口闭合显著改善（第7天分别为32.9 ± 5.0%和11.9 ± 3%，P > 0.05;第14天分别为73.0 ± 6.4%和36.5 ± 7%，P < 0.05;第21天分别为88.0 ± 5.7%和66.7 ± 5%，P > 0.05）。成功的缺血诱导的骨髓PC动员由骨髓SDF-1α水平的转换介导。在糖尿病中，这种转换不会发生。普乐沙福是一种潜在的治疗药物，可通过降低骨髓SDF-1α、恢复正常PC动员和组织愈合来改善糖尿病相关缺血介导的病理学。
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 (Leprdb/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-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α 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-1α 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-1α, restoring normal PC mobilization and tissue healing.
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DOI：
10.1152/ajpheart.00583.2005
发表时间：
2006-01-01
影响因子：
4.8
作者：
Greer, JJM;Ware, DP;Lefer, DJ
通讯作者：
Lefer, DJ
影响因子：
3.6
作者：
Capla, Jennifer M.;Grogan, Raymon H.;Gurtner, Geoffrey C.
通讯作者：
Gurtner, Geoffrey C.
影响因子：
2.6
作者：
Nakamura, Y;Tajima, F;Murawaki, Y
通讯作者：
Murawaki, Y
影响因子：
82.9
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
通讯作者：
Gurtner, GC
影响因子：
7.7
作者：
Loomans, CJM;de Koning, EJP;van Zonneveld, AJ
通讯作者：
van Zonneveld, AJ