The Mobilization and Effect of Endogenous Bone Marrow Progenitor Cells in Diabetic Wound Healing
The Mobilization and Effect of Endogenous Bone Marrow Progenitor Cells in Diabetic Wound Healing
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DOI：
10.3727/096368910x514288
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发表时间：
2010-01-01
影响因子：
3.3
通讯作者：
Orgill, Dennis P.
中科院分区：
文献类型：
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作者：
Fiorina, Paolo;Pietramaggiori, Giorgio;Orgill, Dennis P.
糖尿病患者的伤口愈合受损，仅表现为适度的血管生成和细胞增殖。干细胞可以促进愈合，但对糖尿病创面修复过程中骨髓祖细胞(BM-PC)的动员和功能动力学知之甚少。本研究的目的是探讨糖尿病db/db小鼠BM-PC动员的动力学及其在早期糖尿病创面修复中的作用。创伤后db/db小鼠外周和淋巴组织中循环造血干细胞(LIN(-)、c-Kit(+)、Sca-1(+))较未损伤对照组稳定增加。外周血内皮祖细胞(CD34+)、VEGFR(+)在伤后第6天和第10天分别增加2.5倍和3.5倍。靶向CXCR4-CXCL12轴诱导内源性BM-PC释放和植入增加，同时CXCL12/SDF-1α在伤口中的表达增加。外周和植入的BM-PC水平增加对应于刺激血管生成和细胞增殖，而添加激动剂(GM-CSF)或拮抗剂(ACK2)并不进一步调节伤口愈合。宏观的组织学相关性表明，干细胞水平的增加与伤口再上皮化水平的提高相对应。在创伤后，糖尿病小鼠显示出内源性BM-PC的自然释放，但只有低水平的这些细胞聚集在愈合组织中。需要更高水平的CXCL12/SDF-1α和循环干细胞来增强它们的植入和生物学效应。尽管关于糖尿病BM-PC功能损害的数据存在争议，但在这个模型中，我们的数据显示了这些细胞触发血管生成和细胞增殖的剩余能力。
Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin(-)c-Kit(+)Sca-1(+)) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34(+)VEGFR(+)) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4-CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1 alpha in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BM-PCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1 alpha and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferation.