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Development of novel cell therapy for diabetic-related peripheral artery diseases

开发糖尿病相关外周动脉疾病的新型细胞疗法

基本信息

批准号：
16591259
负责人：
FURUTANI Akira
金额：
$ 2.18万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591259/
关键词：
Therapeutic angiogenesis Diabetes Hyperlipidemia Blood flow Ischemia

项目摘要

Using Zucker fatty rats, a strain characterized by diabetes and hyperlipidemia, we investigated the diabetes- and hyperlipidemia-related impairment of bone marrow mononuclear cells (BMCs) for inducing therapeutic angiogenesis. BMCs from Zucker fatty and normal Zucker lean rats were collected and cultured. Although the characterization and cell survival of BMCs did not differ, the VEGF production, endothelial differentiation, and endothelial cell colony-forming potential of BMCs from Zucker fatty rats were significantly lower than those of BMCs from lean rats. By using an ischemic hindlimb model, we found that the native recovery of induced limb ischemia in the Zucker fatty rats was also significantly worse than that in the lean rats. Furthermore, the expression of 5-hydroxytryptamine (5-HT(2A)) receptors was obviously higher in the Zucker fatty rats than that in the lean rats and was enhanced after limb ischemia. Although the therapeutic potency was lower than with the implantation of BMCs from normal lean rats, the implantation of BMCs from fatty rats could also induce angiogenesis and increase blood flow significantly in the ischemic hindlimbs of Zucker fatty rats. Furthermore, the blood flow in the ischemic hindlimbs was increased by the administration of sarpogrelate, a selective 5-HT(2A)-receptor antagonist. Our results clearly show diabetes- and hyperlipidemia-related dysfunction and impaired potency for inducing angiogenesis of BMCs. However, the implantation of autologous BMCs into ischemic limbs of diabetic and hyperlipidemic rats has induced therapeutic angiogenesis effectively, and blood flow would be enhanced by the administration of a 5-HT(2A)-receptor antagonist.

使用 Zucker 脂肪大鼠（一种以糖尿病和高脂血症为特征的品系），我们研究了与糖尿病和高脂血症相关的骨髓单核细胞 (BMC) 损伤，以诱导治疗性血管生成。收集并培养 Zucker 脂肪大鼠和正常 Zucker 瘦大鼠的 BMC。尽管 BMC 的特征和细胞存活率没有差异，但 Zucker 脂肪大鼠 BMC 的 VEGF 产生、内皮分化和内皮细胞集落形成潜力显着低于瘦大鼠 BMC。通过使用缺血后肢模型，我们发现Zucker脂肪大鼠诱导的肢体缺血的自然恢复也明显差于瘦大鼠。此外，Zucker肥胖大鼠中5-羟色胺(5-HT(2A))受体的表达明显高于瘦大鼠，并且在肢体缺血后增强。虽然治疗效力低于植入正常瘦大鼠的 BMC，但植入脂肪大鼠的 BMC 也能诱导血管生成，并显着增加 Zucker 脂肪大鼠缺血后肢的血流量。此外，给予沙格雷酯（一种选择性5-HT(2A)-受体拮抗剂）可增加缺血后肢的血流量。我们的结果清楚地显示了糖尿病和高脂血症相关的功能障碍以及诱导 BMC 血管生成的能力受损。然而，将自体BMC植入糖尿病和高脂血症大鼠的缺血肢体中可以有效诱导治疗性血管生成，并且通过给予5-HT(2A)受体拮抗剂可以增强血流。