Translational Model of Cell-Based Therapy of r Myocardial Infarction

项目3：心肌梗死细胞治疗的转化模型。 项目3提出开发和测试体内细胞疗法，以改善心脏功能， 梗塞将研究两种治疗方法：1）注射永生化的克隆群体， 骨髓基质细胞（MSC）或其分泌产物，以促进内源性恢复。2)的植入 外源性心肌细胞（CM），有/没有MSC或MSC衍生因子。外源CM将是 从产前心脏收获或从胚胎干细胞（ESC）分化或诱导 多能干细胞（iPSC）。这些研究将首先在发育良好的大鼠模型中进行 研究人员在这个项目中，并允许足够多的动物测试几个 变量一旦在大鼠模型中确定了有益的方案，将其应用于犬模型。 Torok-Storb及其同事在犬模型中的细胞移植方面具有丰富的经验。在 特别是同种异体移植排斥反应的问题和免疫抑制的好处和后果 准确反映患者的这些相同并发症，因此解决这些问题的策略将 临床相关。这个逐步的计划，从老鼠到狗，将限制所需的狗的数量。有 实现这些目标的三个具体目标。 目的1从犬胚胎干细胞中分离培养心肌细胞并鉴定其特性 细胞（ESC）和诱导多能干细胞（iPSC）。目的2将检验MSC促进 内源性修复和血管重建，诱导耐受，并促进心肌细胞的植入， 老鼠模型为此目的，已经产生了永生化和克隆的MSC系，以提供 可以很好地表征并为研究提供一致产品的试剂。犬MSC品系 将鉴定与大鼠MSC系功能类似的细胞，并用于目标3， 狗狗模型这些研究将有助于建立一个强大的大型动物模型，用于开发方案 以及测试用于治疗心肌梗塞的基于细胞的疗法的功效和安全性。

Project 3: Translational Model of Cell-Based Therapy for Myocardial Infarction. Project 3 proposes to develop and test in vivo, cell-based therapies to improve cardiac function following infarction. Two therapeutic approaches will be studied: 1) Injection of immortalized, clonal populations of marrow stromal cells (MSC), or their secreted products, to facilitate endogenous recovery. 2) Engraftment of exogenous cardiomyocytes (CMs), with/without MSC or MSC-derived factors. The exogenous CMs will be harvested from prenatal hearts or differentiated from either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC). These studies will be performed first in a rat model, which is well developed by investigators in this program, and allows for a sufficiently large number of animals to test several variables. Once a beneficial protocol is identified in the rat model it will be applied to the canine model. Torok-Storb and colleagues have extensive experience with cell transplantation in the dog model. In particular the issues of allograft rejection and the benefits and consequences of immunosuppression accurately reflect these same complications in patients, therefore strategies to address these issues will be clinically relevant. This stepwise plan, from rats to dogs, will limit the number of dogs required. There are three specific aims to address these goals. Aim 1 proposes to generate and characterize cardiomyocytes (CM) derived from canine embryonic stem cells (ESC) and from induced pluripotent stem cells (iPSC). Aim 2 will test the hypothesis that MSC facilitate endogenous repair and revascularization, induce tolerance, and promote engraftment of cardiomyocytes in the rat model. For this purpose immortalized and cloned MSC lines have been generated to provide reagents that can be well characterized and provide a consistent product for investigation. Dog MSC lines functionally analogous to rat MSC lines will be identified and used in Aim 3 to repair an infarcted heart in the dog model. These studies will serve to establish a robust large animal model for developing protocols and testing the efficacy and safety of cell based therapies for treating myocardial infarcts.