Stem cell patch therapy in hearts with LV infarction

描述(由申请人提供)： 穿壁性心肌梗死后，为补偿收缩心肌的丧失，发生了左心室重构(LVR)，并伴有腔内扩张和肥厚。虽然可以在一段时间内实现稳定的左室重构，但进行性心肌功能障碍可发展为最终导致明显的充血性心力衰竭(CHF)。目前可用于治疗穿透性左室壁梗死所致心力衰竭的治疗选择有限。最近几项令人兴奋的研究表明，组织特异性干细胞可能具有从无关器官产生组织细胞的能力。我们已经在正常人出生后的骨髓中鉴定出一组具有多向分化和广泛增殖潜能的原始细胞，我们将其命名为多潜能成体祖细胞或MAPC。这项拟议的研究将检验一种新的纤维蛋白贴片将同种异体或自体细胞输送到心肌梗死以改善左心功能和防止过渡到心力衰竭的能力。采用猪心肌梗死后左室重构模型，分别用核磁共振和31P-MR波谱研究细胞移植对左心室收缩功能和心肌能量代谢的影响。将检验以下假设：1)纤维蛋白干细胞贴片可以将高浓度的同种异体MAPC输送到缺血心肌的表面。作为对心肌缺血信号的反应，干细胞将离开纤维蛋白补片，回到缺血心肌中，修复梗死区，防止左室壁瘤的形成。2)纤维蛋白-凝血酶贴片可在30分钟内输送高浓度的自体骨髓干细胞。自体骨髓细胞将逐渐离开贴片，迁移到梗死区，在那里继续分裂分化为肌细胞、平滑肌细胞和内皮细胞，并取代心肌梗死。3)将MAPC包裹在双聚纤维蛋白凝胶中，使细胞在体外部分分化并发展收缩功能，然后移植到梗死区，形成的人工心肌将重建左室收缩功能。通过提供对细胞补片移植效果的洞察，结果可能导致更好的左室损伤的预防、诊断和治疗方法。

DESCRIPTION (provided by applicant): Following transmural myocardial infarction left ventricular remodeling (LVR) with chamber dilation and hypertrophy occurs to compensate for loss of contracting myocardium. Although stable LV remodeling may be achieved for a period of time, progressive myocardial dysfunction can develop and ultimately lead to overt congestive heart failure (CHF). The currently available therapeutic options for heart failure due to transmural left ventricular infarct are limited. Several exciting recent studies have shown that tissue specific stem cells may have the ability to generate cells of tissues from unrelated organs. We have identified a population of primitive cells in normal human post-natal bone marrow that have multipotent differentiation and extensive proliferation potential, which we have named Multipotent Adult Progenitor Cells or MAPC. The proposed research will examine the ability of a novel fibrin patch to deliver allogenic or autologous cells into myocardial infarcts to improve LV function, and to prevent the transition to heart failure. Using a swine model of postinfarction LV remodeling, the effect of cell transplantation on LV contractile function and myocardial energy metabolism will be examined using MRI and 31P-MR spectroscopy, respectively. The following hypothesis will be tested: 1) A fibrin-stem cell patch can deliver a high concentration of allogenic MAPC onto the surface of ischemic myocardium. In response to myocardial ischemic signals, the stem cells will leave the fibrin patch and home to the ischemic myocardium to repair the infarct region and to prevent the formation of LV aneurysm. 2) A fibrin-thrombin patch can be used to deliver a high concentration of autologous bone marrow stem cells within 30 minutes. The autologous bone marrow cells will gradually leave the patch and migrate to the infarct area where they continue to divide and differentiate into myocytes, smooth muscle cells and endothelial cells, and replace the myocardial infarct. 3) An artificial myocardium generated by entrapping MAPC in a bipolymer fibrin gel and allowing the cells to partially differentiate and develop contractile function in vitro before implantation onto the infarct region will reestablish LV contractile function. By providing insight into the effects of the cellular patch transplantation, the results may lead to better preventive, diagnostic and therapeutic modalities for LV injury.