Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing.
Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing.
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DOI：
10.1097/sla.0b013e3181f5a079
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发表时间：
2010-10
影响因子：
9
通讯作者：
Velazquez OC
中科院分区：
文献类型：
--
作者：
Liu ZJ;Tian R;An W;Zhuge Y;Li Y;Shao H;Habib B;Livingstone AS;Velazquez OC
我们以前报道过，基质细胞衍生因子-1 α（SDF-1α，一种将内皮祖细胞（EPC）募集到新血管形成区域的归巢信号）在糖尿病伤口中下调。我们现在研究成熟内皮细胞（EC）和循环EPC实现SDF-1α介导的EPC归巢的信号。通过注射SDF-1α工程化骨髓源成纤维细胞与对照细胞相比，糖尿病伤口中的SDF-1α在治疗上增加（N= 48（20，NOD），（28，STZ-C57））。PCR-阵列基因表达差异通过Western印迹和免疫组织化学进行验证。采用拮抗剂进一步研究了粘附分子在介导SDF-1α诱导的EPC归巢和伤口愈合中的作用。通过细胞基础疗法增加伤口SDF-1α可促进糖尿病小鼠的愈合（第3天愈合率增加约20%，p=0.006）。SDF-1α增加EC-EPC粘附，并特异性上调人微血管EC中E-选择素的表达（增加2.3倍，p<0.01）。这种效应在实验小鼠的血管中也很显著，并导致伤口新血管形成增加。SDF-1α对EC-EPC粘附和EPC归巢的调节作用是由E-选择素特异性介导的，因为E-选择素拮抗剂的应用显著抑制了SDF-1α诱导的EC-EPC粘附、EPC归巢、伤口新生血管形成和伤口愈合。基于SDF-1α工程化细胞的治疗通过特异性上调成熟EC中的E-选择素表达，导致EC-EPC粘附增加、EPC归巢和伤口新血管形成增加，从而促进小鼠糖尿病伤口愈合。这些发现为SDF-1α对EPC归巢的生物学效应的潜在信号提供了新的见解，并指出E-选择素作为糖尿病伤口愈合中EPC运输治疗操纵的新的潜在靶点。
We previously reported that stromal cell-derived factor-1α (SDF-1α, a homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds . We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1α-mediated EPC homing. SDF-1α in diabetic wounds were therapeutically increased by injection of SDF-1α–engineered bone marrow-derived fibroblasts versus control cells (N= 48 (20, NOD), (28, STZ-C57)). PCR-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1α-induced EPC homing and wound healing was furthered studied using antagonists in vitro and in vivo. Increasing wound SDF-1α via cell-base therapy promotes healing in diabetic mice (~20% increase in healing rates by day 3, p=0.006). SDF-1α increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular EC (2.3-fold increase, p<0.01). This effect was also significant in blood vessels of the experimental mice and resulted in increased wound neovascularization. The regulatory effects of SDF-1α on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1α-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing. SDF-1α–engineered cell-based therapy promotes diabetic wound healing in mice by specifically upregulating E-selectin expression in mature EC leading to increase EC-EPC adhesion, EPC homing and increased wound neovascularization. These findings provide novel insight into the signals underlying the biological effect of SDF-1α on EPC homing and point to E-selectin as a new potential target for therapeutic manipulation of EPC trafficking in diabetic wound healing.