Dextran induces differentiation of circulating endothelial progenitor cells.
Dextran induces differentiation of circulating endothelial progenitor cells.
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DOI：
10.1002/phy2.261
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发表时间：
2014
影响因子：
2.5
通讯作者：
Asahara, Takayuki
中科院分区：
文献类型：
--
作者：
Obi, Syotaro;Masuda, Haruchika;Akimaru, Hiroshi;Shizuno, Tomoko;Yamamoto, Kimiko;Ando, Joji;Asahara, Takayuki
内皮祖细胞（EPCs）已被证明是有效的治疗心血管疾病。然而，从循环到粘附的分化过程尚未明确，因为以前在EPC培养中循环的EPCs很少附着在培养皿上。在这里，我们研究了未成熟的循环EPCs是否会在葡聚糖的作用下分化为成熟的粘附EPCs。用5%和10%葡聚糖培养从体外扩增的人脐带血中提取的漂浮循环EPCs，它们附着在纤维连接蛋白包被的培养皿上并呈指数增长。右旋糖酐使EPCs的粘附、增殖、迁移、成管和分化型集落形成的生物活性增加。内皮标志物血管内皮生长因子（VEGF）‐R1/2、VE‐cadherin、Tie2、ICAM1、VCAM1和整合素αv/β3的表面蛋白表达率在暴露于葡聚糖的EPCs中升高。VEGF‐R1/2、VE‐cadherin、Tie2、内皮一氧化氮合酶、MMP9和VEGF mRNA水平在葡聚糖处理的EPCs中升高。内皮相关转录因子ID1/2、FOXM1、HEY1、SMAD1、FOSL1、NFkB1、NRF2、HIF1A、EPAS1在葡聚糖处理的EPCs中表达增加；然而，造血和抗血管生成相关转录因子TAL1， RUNX1, c - MYB, GATA1/2， ERG, FOXH1， HHEX， SMAD2/3在葡聚糖暴露的EPCs中降低。抑制剂分析表明，PI3K/Akt、ERK1/2、JNK和p38信号转导通路参与了葡聚糖的分化。总之，葡聚糖诱导循环EPCs在粘附、迁移、增殖和血管发生方面的分化。葡聚糖的分化机制受多种信号转导调控，包括PI3K/Akt、ERK1/2、JNK和p38。这些发现表明右旋糖酐是再生医学中治疗EPCs的有效方法。
Endothelial progenitor cells (EPCs) have been demonstrated to be effective for the treatment of cardiovascular diseases. However, the differentiation process from circulation to adhesion has not been clarified because circulating EPCs rarely attached to dishes in EPC cultures previously. Here we investigated whether immature circulating EPCs differentiate into mature adhesive EPCs in response to dextran. When floating‐circulating EPCs derived from ex vivo expanded human cord blood were cultured with 5% and 10% dextran, they attached to fibronectin‐coated dishes and grew exponentially. The bioactivities of adhesion, proliferation, migration, tube formation, and differentiated type of EPC colony formation increased in EPCs exposed to dextran. The surface protein expression rate of the endothelial markers vascular endothelial growth factor (VEGF)‐R1/2, VE‐cadherin, Tie2, ICAM1, VCAM1, and integrin αv/β3 increased in EPCs exposed to dextran. The mRNA levels of VEGF‐R1/2, VE‐cadherin, Tie2, endothelial nitric oxide synthase, MMP9, and VEGF increased in EPCs treated with dextran. Those of endothelium‐related transcription factors ID1/2, FOXM1, HEY1, SMAD1, FOSL1, NFkB1, NRF2, HIF1A, EPAS1 increased in dextran‐treated EPCs; however, those of hematopoietic‐ and antiangiogenic‐related transcription factors TAL1, RUNX1, c‐MYB, GATA1/2, ERG, FOXH1, HHEX, SMAD2/3 decreased in dextran‐exposed EPCs. Inhibitor analysis showed that PI3K/Akt, ERK1/2, JNK, and p38 signal transduction pathways are involved in the differentiation in response to dextran. In conclusion, dextran induces differentiation of circulating EPCs in terms of adhesion, migration, proliferation, and vasculogenesis. The differentiation mechanism in response to dextran is regulated by multiple signal transductions including PI3K/Akt, ERK1/2, JNK, and p38. These findings indicate that dextran is an effective treatment for EPCs in regenerative medicines.