Stem Cell Therapy for Myocardial Repair

摘要 心肌梗死常引起一段时间的左心室（LV）重构。当LV重构发生时， 血流动力学稳定的初始阶段之后是LV功能障碍的发展，可能导致 充血性心力衰竭（CHF）。进行性心力衰竭的分子和细胞基础是 受损和凋亡的肌细胞不能被替换。虽然有相当数量的 在最近关于使用不同类型的干细胞进行心肌修复的细胞疗法的文献中， 移植率以及心肌细胞再生率低是心肌细胞治疗中的主要问题。 拟议的研究将利用来自人诱导的预分化的肌细胞和血管细胞， 多能干细胞（hiPSC）在具有免疫抑制的梗死后LV重构的猪模型中的作用， 我们先前已经证明其与人类临床心脏再生治疗非常相关。这里我们 将致力于实现以下具体目标。具体目标1：使用亚微米3D打印来制造基于ECM的 基于ECM在天然心肌中的分布的水凝胶，以产生心肌组织等效物 具有增强的iPSC衍生的三系心脏细胞类型的功能。目标2：最近使用 建立T1-nom P-31磁化饱和转移（MST）和2D化学位移成像（2D-CSI） 方法检查是否心肌ATP通量率通过CK和ATP酶是最严重的改变 在梗死心脏的边缘区内膜下层（ENDO）中。减少的严重程度 心肌梗死后，通过CK和ATP酶的ENDO产生ATP的能力与心肌梗死的严重程度呈线性相关。 左心室功能障碍具体目标3：检查移植的功能性有益作用是否 使用人iPSC-CM的新型ECM组织等同物，-内皮细胞（EC）和-平滑肌细胞（SMC） 伴随着移植细胞向心肌的保留和整合的增强， 减少左室壁应力，这反过来又导致心肌ATP生产储备的改善，通过这两个 心肌梗死后心内膜组织中CK和ATP酶的变化。这些研究的结果可能会导致更好的诊断和 急性心肌梗死的治疗方式。

ABSTRACT Myocardial infarction often induces a period of left ventricular (LV) remodeling. When LV remodeling occurs, an initial period of hemodynamic stability is followed by the development of LV dysfunction that may result in congestive heart failure (CHF). The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged and apoptotic myocytes to be replaced. Although there are a significant number of reports in recent literature on cellular therapy for myocardial repair using different type of stem cells, the low engraftment rate, as well as the low cardiomyocytes regeneration are the major problems in cardiac cell therapy. The proposed studies will utilize pre differentiated myocytes and vascular cells derived from human induced pluripotent stem cells (hiPSCs) in a porcine model of postinfarction LV remodeling with immune suppression that we have previously demonstrated to be very relevant to human clinical cardiac regenerative therapies. Here we will pursue the following specific aims. Specific Aim 1: To use submicron 3D printing to fabricate ECM-based hydrogels based on the distribution of ECM in the native myocardium to generate a myocardial tissue equivalent with enhanced function of iPSC-derived tri-lineage cardiac cell types. Specific Aim 2: Using the recently established T1-nom P-31 magnetization saturation transfer (MST) and 2D chemical shifting imaging (2D-CSI) methods to examine whether the myocardial ATP flux rate via both CK and ATPase are most severely altered in the periscar border zone subendocardial layers (ENDO) of infarcted hearts. The severity of the decrease in ATP production capacity via CK and ATPase in ENDO of the infarcted heart is linearly related to the severity of the LV dysfunction. Specific Aim 3: To examine whether the functional beneficial effects of transplantation of the novel ECM tissue equivalent using human iPSC-CM, -endothelial cells (EC) and –smooth muscle cells (SMC) are accompanied by enhanced retention and integration of transplanted cells to the myocardium and associated reduction of LV wall stress, which in turn results in improvement of myocardial ATP production reserve via both CK and ATPase in the ENDO of infarcted hearts. The results of these studies may lead to better diagnostic and therapeutic modalities for acute myocardial infarction.