Stem Cell Therapy and Postinfarction LV Remodeling

描述（由申请人提供）：充血性心力衰竭通常被认为是一种终末期不可逆临床疾病，其医学管理主要是缓解症状和减缓进展。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。这种出乎意料的可塑性是否构成了“转分化”，或者是否有一小群多能干细胞在出生后的组织中持续存在，目前还不清楚。最近，有越来越多的报道，细胞治疗改善心肌梗死小鼠心脏的左室功能。然而，细胞植入率通常较低，范围为0.3%-3%，取决于动物模型和递送模式。因此，大多数移植到心脏的细胞不能成功移植。此外，大多数移植的细胞不分化成宿主心脏细胞表型。因此，迫切需要增强MSC植入并增加其增殖和分化为功能性心肌细胞的速率的方法。利用骨髓间充质干细胞（MSC），本研究计划将在猪梗死后左室重构模型中研究可能的心脏修复细胞疗法的机制。将通过心脏MRI测量干细胞移植对LV收缩功能的功能后果，通过31 P和1H-MR光谱测量心肌能量代谢和氧合水平，以及通过微球测量心肌最大血流储备。该项目的具体目标是： SA 1.为了确定生长因子增强的自体骨髓间充质干细胞移植在梗死时的疗效以及短期有益效果是否持久，即。4周时存在的治疗效果是否将在移植后持续约4个月。 SA 2.确定延迟的生长因子增强的自体MSC移植（梗死后4周）是否比梗死时移植更有效，以及延迟移植的治疗效果是否持久。 SA 3.为了确定部分预分化的心肌细胞和内皮细胞的混合物（在移植前暴露于相应的分化方案7天）加上生长因子是否比注射未分化的MSC具有更大的有益效果。 SA 4.为了确定心肌注射储存的同种异体MSC（加生长因子）是否有益！效果与自体MSC相当。 SA 5.为了确定MSC在共价结合生长因子（HGF和IGF）的三维多孔可生物降解的PEG化纤维蛋白基质中的移植是否会提高MSC的移植率。因此也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.