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

胎盘生长因子（PlGF）是fit-1的特异性配体，已知可刺激单核细胞从骨髓向损伤组织募集，并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。本研究探讨了急性心肌梗死患者和小鼠模型中PlGF的表达模式以及PlGF对临床病程的影响。方法和结果：人类研究：55例急性心肌梗死患者和43例对照。在闭塞的冠状动脉再通术（RC）前后，分别从周围静脉、冠状动脉口（CA）和冠状动脉窦（CS）采血，ELISA法测定血浆PlGF水平。心肌梗死后血浆PlGF （[CS]-[CA]）的经心梯度显著高于缺血前（14.1±10.6 vs, 0.0±1.1pg/ml p<0.01），表明心肌产生和释放更多的PlGF。血浆PlGF峰值水平（3.2±1.1 d）显著高于对照组（35.1±26.5 pg/ml vs 13.4±5.7 pg/ml, p<0.001）。心肌梗死急性期血浆PlGF峰值水平与外周血单核细胞计数峰值呈正相关（r=0.42,p<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，PlGF是6个月随访研究中左室射血分数恢复的最强独立预测因子（p=0.0098）。小鼠研究：心肌梗死小鼠模型中，组织PlGF mRNA表达较假手术心脏增加26.6倍（p<0.001）。免疫组化染色显示PlGF蛋白主要在梗死区冠状动脉内皮细胞过表达，而在非梗死区几乎不表达。结论：心肌梗死急性期心肌组织尤其是梗死区冠状动脉内皮细胞快速产生PlGF，过表达PlGF可能通过募集骨髓单核细胞参与慢性期左室功能的改善。少

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