Stem Cell Therapy and Postinfarction LV Remodeling

描述(申请人提供)：充血性心力衰竭通常被认为是一种终末期不可逆转的临床状况，药物治疗主要是缓解症状和缓慢进展。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。这种意想不到的可塑性是否构成了“转分化”，或者一小部分多能干细胞是否在出生后组织中持续存在，目前尚不清楚。最近，有越来越多的报道称细胞疗法改善了心肌梗死小鼠的左心功能。然而，细胞植入率通常很低，根据动物模型和分娩方式的不同，植入率在0.3%-3%之间。因此，大多数移植到心脏的细胞都没有成功植入。此外，大多数移植细胞不能分化为宿主心肌细胞表型。因此，迫切需要加强MSCs植入、提高其增殖和分化为功能心肌细胞的方法。利用骨髓间充质干细胞(MSC)，这项研究计划将探讨一种可能的细胞疗法在猪心肌梗死后左室重构模型中用于心脏修复的机制。干细胞移植对左心室收缩功能的功能影响将通过心脏核磁共振测量，心肌能量代谢和氧合水平由31P-和1H-MR波谱测量，心肌最大血流储备由微球测量。该项目的具体目标是： SA1.目的：确定梗死时生长因子增强的自体骨髓间充质干细胞移植的疗效，以及短期疗效是否持久。移植后4周的疗效是否能持续4个月。 SA2.为了确定延迟的生长因子增强的自体MSCs移植(梗塞后4周)是否比梗塞时的移植更有效，以及延迟移植的治疗效果是否持久。 SA3.为了确定心肌梗死是否在部分预分化的心肌细胞和内皮细胞的混合物上(移植前在各自的分化方案中暴露7天)加上生长，这些因素将比注射未分化的MSCs具有更大的益处。 SA4.以确定心肌注射异体骨髓间充质干细胞(Fplus生长因子)是否会有好处！效果与自体骨髓间充质干细胞相当。 SA5.目的：确定将MSC移植到共价结合生长因子(HGF和IGF)的多孔可生物降解聚乙二醇胺纤维蛋白基质中是否能提高MSCs的成活率。也因此带来了功能上的好处。

DESCRIPTION (provided by applicant): Congestive heart failure has generally been considered an end-stage irreversible clinical condition for which medical management is principally to relieve symptoms and slow progression. Several exciting recent studies have shown that tissue specific stem cells may have the ability to generate cells of tissues from unrelated organs. Whether this unexpected plasticity constitutes "trans differentiation" or whether a small population of multi potent stem cells persists in post-natal tissues is not known. Recently, there is an increased volume of reports that cellular therapy improves LV function in murine hearts with myocardial infarction. However, the cell engraftment rate is usually low and ranges from 0.3%-3% depending upon the animal models and modes of the delivery. Hence, the majority of cells transplanted to the heart do not successfully engraft. Further, most engrafted cells do not differentiate into host cardiac cell phenotypes. Therefore, methods to enhance MSCs engraftment and increase their rates of proliferation and differentiation into functioning cardiomyocytes are urgently needed. Using bone marrow derived mesenchymal stem cells (MSC), this research proposal will examine the mechanisms of a possible cellular therapy for cardiac repair in a swine model of postinfarction LV remodeling. The functional consequences of stem cell transplantation on LV contractile function will be measured by cardiac MRI, myocardial energy metabolism and oxygenation levels measured by 31P- and 1H- MR spectroscopy, and myocardial maximum blood flow reserve by microspheres. The specific aims of this project are: SA1. To determine the efficacy of growth factor enhanced autologous MSCs transplantation at the time of infarction and whether short term beneficial effects are durable, i.e.. whether therapeutic effects present at 4 weeks will persist for -4 months post-transplantation . SA2. To determine if delayed, growth factor enhanced autologous MSCs transplantation (4 weeks post-Infarction) is more effective than transplantation at the time of infarction and whether the therapeutic effects of delayed transplantation are durable. SA3. To determine whether myocardial inlectlon a mixture of partially pre-differentiated cardlomvocvtes and endothelium (exposure to the respective differentiation protocols for 7 days before transplantation) plus growth ,' factors will have greater beneficial effects than injection of undifferentiated MSCs. SA4. To determine whether myocardial injection of banked alloqenic MSCs fplus growth factors) will have beneficial ! effects comparable to those of autoloqous MSCs. SA5. To determine whether transplantation of MSC in a thretf-dimensional porous biodegradable PEGvlated fibrin \ matrix that covalentlv binds the growth factors (HGF and IGF) will enhance the rate, of MSCs enqraftment. and therefore functional benefits.