Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells
Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells
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DOI：
10.1161/01.res.0000099245.08637.ce
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发表时间：
2003-11-14
影响因子：
20.1
通讯作者：
Matsubara, H
中科院分区：
文献类型：
--
作者：
Fujiyama, S;Amano, K;Matsubara, H
外周血（PB）来源的CD14（+）单核细胞被证明转分化为内皮细胞（EC）谱系细胞，并有助于新血管形成。我们研究了颈动脉球囊损伤后骨髓（BM）或外周血来源的CD34（-）/CD14（+）细胞是否参与了再内皮化。虽然造血干细胞和间充质干细胞都不包括在人BM来源的CD34（-）/CD14（+）单核细胞谱系细胞（BM-MLC）中，但它们表达与成熟EC相同程度的EC特异性标志物（Tie2、CD31、VE-钙粘蛋白和内皮糖蛋白）。当BM-MLCs与血管内皮生长因子一起培养时，造血标记物急剧减少，并诱导新的EC特异性标记物（Flk和CD34）。将BM-MLCs动脉内移植到无胸腺裸大鼠球囊损伤的动脉中。在体内或体外，单核细胞趋化蛋白-1（MCP-1）激活BM-MLCs后，BM-MLCs粘附于损伤的血管内皮上，通过失去造血标志物分化为EC样细胞，抑制新生内膜增生。CD34（+）细胞对新生内膜增生的抑制作用强于骨髓来源的CD34（+）细胞。在PB来源的CD34（-）/CD14（+）单核细胞中未观察到MCP依赖性粘附。再生的内皮呈现鹅卵石外观，阻断染料外渗，并诱导NO依赖性血管舒张。与PB来源的单核细胞相比，BM-MLC在层流下对HUVEC的基础粘附活性和β（1）-整合素表达（基础和活性形式）显著增加。MCP-1通过激活β（1）-整合素构象显著增强BM-MLCs对HUVECs的粘附活性（2.8倍）。因此，BM-MLCs可以作为EC祖细胞发挥功能，其比CD34（+）细胞更有效，并获得以MCP-1依赖性方式粘附在受损内皮上的能力，导致与抑制内膜增生相关的再内皮化。这将为MCP-1介导的生物学作用和细胞治疗的血管再生策略打开一扇新的窗口。
Peripheral blood (PB)-derived CD14(+) monocytes were shown to transdifferentiate into endothelial cell (EC) lineage cells and contribute to neovascularization. We investigated whether bone marrow (BM)- or PB-derived CD34(-)/CD14(+) cells are involved in reendothelialization after carotid balloon injury. Although neither hematopoietic nor mesenchymal stem cells were included in human BM-derived CD34(-)/CD14(+) monocyte lineage cells (BM-MLCs), they expressed EC-specific markers (Tie2, CD31, VE-cadherin, and endoglin) to an extent identical to mature ECs. When BM-MLCs were cultured with vascular endothelial growth factors, hematopoietic markers were drastically decreased and new EC-specific markers (Flk and CD34) were induced. BM-MLCs were intra-arterially transplanted into balloon-injured arteries of athymic nude rats. When BM-MLCs were activated by monocyte chemoattractant protein-1 (MCP-1) in vivo or in vitro, they adhered onto injured endothelium, differentiated into EC-like cells by losing hematopoietic markers, and inhibited neointimal hyperplasia. Ability to prevent neointimal hyperplasia was more efficient than that of BM-derived CD34(+) cells. MCP-dependent adhesion was not observed in PB-derived CD34(-)/CD14(+) monocytes. Regenerated endothelium exhibited a cobblestone appearance, blocked extravasation of dye, and induced NO-dependent vasorelaxation. Basal adhesive activities on HUVECs under laminar flow and beta(1)-integrin expression ( basal and active forms) were significantly increased in BM-MLCs compared with PB-derived monocytes. MCP-1 markedly enhanced adhesive activity of BM-MLCs (2.8-fold) on HUVECs by activating beta(1)-integrin conformation. Thus, BM-MLCs can function as EC progenitors that are more potent than CD34(+) cells and acquire the ability to adhere on injured endothelium in a MCP-1 -dependent manner, leading to reendothelialization associated with inhibition of intimal hyperplasia. This will open a novel window to MCP-1-mediated biological actions and vascular regeneration strategies by cell therapy.