Integrated study of bone marrow derived multipotent stem cell in the wound healing process of acute myocardial infarction

骨髓源性多能干细胞在急性心肌梗死创面愈合过程中的综合研究

• 批准号: 15590767
• 负责人: UEMURA Shiro
• 金额: $ 1.92万
• 依托单位: Nara Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590767/
• 关键词: Myocardial Infarction; Regeneration Medicine; Placental Growth Factor; Wound Healing; Stem Cell; 骨髄

Placental growth factor(PlGF), a specific ligand for fit-1, is known to stimulate the recruitment of monocyte from bone marrow into the injured tissue, and seems to enhance wound healing processes by activating monocyte and inducing arteriogenesis. However, clinical significance of PlGF in myocardial infarction(MI) has not been understood. This study investigated expression pattern of PlGF and the impact of PlGF on the clinical course in patients and mouse models of acute MI. Methods and Results : Human study : Fifty five patients with acute MI and 43 controls were enrolled. Blood sampling was performed from peripheral vein, ostium of coronary artery(CA), and coronary sinus(CS), before and after recanalization(RC) of occluded CA. Plasma levels of PlGF were measured by ELISA. Transcardiac gradient of plasma PlGF ([CS]-[CA]) just after RC of the occluded CA was significantly higher than the value before RC (14.1±10.6 vs, 0.0±1.1pg/ml p<0.01), indicating cardiac production and release of … More PlGF from infarct heart. Peak plasma PlGF levels (3.2±1.1 days) were significantly higher than those in control subjects (35.1±26.5 pg/ml vs 13.4±5.7 pg/ml, p<0.001). Peak plasma PlGF levels positively correlated with peak peripheral monocyte counts during acute phase of MI (r=0.42,p<0.005), although they did not correlated with age, gender, time to reperfusion, or peak CK-MB. Furthermore, multiple regression analysis revealed that PlGF was the strongest independent predictor for the restoration of left ventricular ejection fraction examined at 6-month follow-up study (p=0.0098). Mouse study : In mouse models of MI, tissue PlGF mRNA expression was increased 26.6 fold (p<0.001) compared with sham operated heart. Immunohistochemical staining showed that PlGF protein was over-expressed mainly in endothelial cells of coronary artery in the infarct region, but scarcely in non-infarct region. Conclusion : PlGF is rapidly produced in the infarct myocardial tissue, especially endothelial cells of coronary artery in infarct region during acute phase of MI, and over-expressed PlGF seems to be involved in the improvement of left ventricular function in chronic phase probably by recruiting monocyte from bone marrow. Less

胎盘生长因子(PlGF)是FIT-1的特异性配体，能刺激骨髓中的单核细胞向损伤组织募集，似乎通过激活单核细胞和诱导动脉生成来促进伤口愈合过程。然而，PlGF在心肌梗死(MI)中的临床意义尚不清楚。本研究探讨了PlGF在急性心肌梗死患者和小鼠模型中的表达模式及其对临床病程的影响。方法和结果：人体研究：纳入55例急性心肌梗死患者和43例正常对照。分别于冠脉再通(RC)前、后外周静脉、冠脉口(CA)和冠状静脉窦(CS)采血。采用双抗体夹心酶联免疫吸附试验检测血浆PlGF水平。冠脉结扎后即刻血浆血小板生长因子([CS]-[CA])的跨心梯度显著高于冠脉阻断前(14.1±10.6 vs，0.0±1.1pg/mlp&lt；0.0 1)，提示心脏产生和释放…更多的PlGF来自于心肌梗死。血浆血小板生长因子峰值(3.2d±1.1d)显著高于对照组(35.1±26.5pg/mlvs13.4±5.7pg/mlp&lt；0.001)。急性心肌梗死急性期血浆血小板生长因子峰值水平与外周血单核细胞峰值计数呈正相关(r=0.42p&lt；0.005)，但与年龄、性别、再灌注时间或CK-MB峰值无关。此外，多元回归分析显示，在6个月的随访研究中，血小板生长因子是影响左心室射血分数恢复的最强独立预测因素(p=0.0098)。小鼠研究：在心肌梗死小鼠模型中，与假手术心脏相比，组织PlGF mRNA的表达增加了26.6%(p&lt；0.001)。免疫组织化学染色显示，PLGF蛋白主要在梗死区的冠状动脉内皮细胞中过度表达，而在非梗死区几乎不表达。结论：MI急性期梗死区心肌组织，尤其是梗死区冠状动脉内皮细胞迅速产生PlGF，慢性期高表达的PlGF可能通过向骨髓募集单核细胞参与改善左心功能。较少