Mobilization of endothelial progenitor cells in fracture healing and distraction osteogenesis
Mobilization of endothelial progenitor cells in fracture healing and distraction osteogenesis
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DOI：
10.1016/j.bone.2008.01.007
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发表时间：
2008-05-01
期刊：
影响因子：
4.1
通讯作者：
Choi, In Ho
中科院分区：
文献类型：
--
作者：
Lee, Dong Yeon;Cho, Tae-Joon;Choi, In Ho
简介：骨折愈合和牵张成骨（DO）是出生后独特的骨形成过程，成功的骨再生关键需要新血管形成。我们研究了骨再生过程中内皮祖细胞（EPC）的动员，以及EPCs对血管化和新骨形成的可能贡献，特别是在DO.Methods：小鼠胫骨骨折和大鼠胫骨DO模型在这项研究中使用。通过检测内皮细胞系染色特征和EPC细胞表面标志物来确定EPC在外周血和脾单个核细胞（NINCs）中的比例。通过核糖核酸酶保护试验和逆转录聚合酶链反应分析了骨折部位与EPC动员和归巢相关分子的信使RNA表达。在大鼠胫骨DO模型中，我们测量血流量DO期间，并确定体外扩增和静脉内输注的EPCs的分布。结果：EPCs之间的外周和脾脏MNCs骨折后增加的比例，骨折后第3天达到峰值，并恢复到基础水平在愈合期间。EPC动员细胞因子，如血管内皮生长因子（VEGF），干细胞因子，单核细胞趋化蛋白-1，和基质细胞衍生因子-1，在骨折骨痂的信使RNA表达上调。血浆VEGF水平在EPC比例增加之前达到峰值。参与EPC归巢的粘附分子在骨折骨痂中表达。在DO模型中，EPC比例增加的时间模式与骨折愈合模型中的相似，但EPC比例在牵引和固结阶段再次增加。在牵张阶段，牵张间隙相对缺血，在巩固阶段，血流量大量增加。在DO模型中，EPCs归巢到骨再生位点的数量与移植EPCs的数量呈剂量依赖性相关。结论：这些研究结果表明，来自骨再生位点的信号将EPCs从骨髓动员到外周循环中。增加EPC动员和归巢可能有助于新血管形成，从而在骨折愈合和DO的新骨形成。(c)2008年爱思唯尔公司All rights reserved.
Introduction: Fracture healing and distraction osteogenesis (DO) are unique postnatal bone formation processes, and neovascularization is critically required for successful bone regeneration. We investigated endothelial progenitor cell (EPC) mobilization during bone regeneration, and the possible contribution of EPCs to increased vascularization and new bone formation, especially in DO.Methods: Mouse tibia fracture and rat tibia DO models were used in this study. The proportion of EPCs among the peripheral and splenic mononuclear cells (NINCs) was determined by examining the endothelial lineage staining characteristics and EPC cell surface markers. Messenger RNA expression of molecules related to EPC mobilization and homing at the fracture site were analyzed by ribonuclease protection assay and reverse-transcription polymerase chain reaction. In the rat tibia DO model, we measured blood flow during DO, and determined the distribution of ex vivo-expanded and intravenously-infused EPCs.Results: The proportion of EPCs among the peripheral and splenic MNCs increased after fracture, peaked on post-fracture day 3, and returned to basal levels during the healing period. Messenger RNA expression of EPC mobilizing cytokines such as vascular endothelial growth factor (VEGF), stem cell factor, monocyte chemoattractant protein-1, and stromal cell-derived factor-1, were upregulated at the fracture callus. The plasma VEGF levels peaked prior to the increase in the EPC proportion. Adhesion molecules involved in EPC homing were expressed at the fracture callus. In the DO model, the temporal pattern of the increase in the EPC proportion was similar to that in the fracture healing model, but the EPC proportion increased again during the distraction and consolidation phases. The distraction gap was relatively ischemic during the distraction phase and blood flow increased profusely later in the consolidation phase. The number of EPCs homing to the bone regeneration site in the DO model correlated with the number of transplanted EPCs in a dose-dependent manner.Conclusions: These findings suggest that signals from the bone regeneration site mobilize EPCs from the bone marrow into the peripheral circulation. Increased EPC mobilization and homing may contribute to neovascularization and thus to new bone formation in fracture healing and DO. (c) 2008 Elsevier Inc. All rights reserved.