Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms
Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms
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DOI：
10.1161/01.cir.0000124062.31102.57
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发表时间：
2004-03-30
期刊：
影响因子：
37.8
通讯作者：
Epstein, SE
中科院分区：
文献类型：
--
作者：
Kinnaird, T;Stabile, E;Epstein, SE
背景-据报道，骨髓细胞治疗通过细胞并入新血管或重塑血管而促进侧枝形成。然而，旁分泌对这一效应的可能作用还不太清楚。方法与结果-采用培养骨髓磁珠分离纯化小鼠骨髓源性基质细胞（MSCs）。通过对MSC条件培养基（MSC- cm）的分析，证实了血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、胎盘生长因子（PlGF）和单核细胞趋化蛋白-1 （MCP-1）的释放。MSC-CM以剂量依赖性方式增强内皮细胞和平滑肌细胞的增殖；抗vegf和抗fgf抗体只能部分减弱这些作用。Balb/C小鼠（n = 10）行股远端动脉结扎，24小时后内收肌注射1 × 106个MSCs。与注射培养基（n = 10）或成熟内皮细胞（n - 8）的对照组相比，远端肢体灌注改善，大腿中部传导血管数量和总横截面积增加。骨髓间充质干细胞注射改善了肢体功能和外观，减少了自截肢的发生率，减轻了肌肉萎缩和纤维化。注射后，标记的MSCs分散在肌纤维之间，但未见并入成熟的络。与对照组相比，注射MSCs增加了内收肌中bFGF和VEGF蛋白的水平。最后，VEGF和移植的MSCs在内收肌组织内共定位被证实。结论-间充质干细胞分泌多种动脉生成细胞因子。间充质干细胞可以通过旁分泌机制促进侧枝重塑。
Background - Bone marrow cell therapy is reported to contribute to collateral formation through cell incorporation into new or remodeling vessels. However, the possible role of a paracrine contribution to this effect is less well characterized.Methods and Results - Murine marrow-derived stromal cells (MSCs) were purified by magnetic bead separation of cultured bone marrow. The release of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced proliferation of endothelial cells and smooth muscle cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects. Balb/C mice (n = 10) underwent distal femoral artery ligation, followed by adductor muscle injection of 1 x 106 MSCs 24 hours later. Compared with controls injected with media (n = 10) or mature endothelial cells (n - 8), distal limb perfusion improved, and mid- thigh conductance vessels increased in number and total cross-sectional area. MSC injection improved limb function and appearance, reduced the incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After injection, labeled MSCs were seen dispersed between muscle fibers but were not seen incorporated into mature collaterals. Injection of MSCs increased adductor muscle levels of bFGF and VEGF protein compared with controls. Finally, colocalization of VEGF and transplanted MSCs within adductor tissue was demonstrated.Conclusions - MSCs secrete a wide array of arteriogenic cytokines. MSCs can contribute to collateral remodeling through paracrine mechanisms.