Stem Cell Therapy for Myocardial Repair

摘要 心肌梗死通常会导致一段时间的左心室(LV)重构。当发生左室重构时， 血流动力学稳定的初期之后是左心功能不全的发展，这可能导致 充血性心力衰竭。进行性心力衰竭的分子和细胞基础是 受损和凋亡的心肌细胞不能被替代。尽管有相当数量的 最近的文献报道了使用不同类型的干细胞进行心肌修复的细胞治疗， 植入率和心肌细胞再生率低是心肌细胞治疗的主要问题。 拟议的研究将利用来自人类诱导的预分化的心肌细胞和血管细胞。 多能干细胞(HiPSCs)在猪脑梗塞后左室重构免疫抑制模型中的作用 我们之前已经证明了与人类临床心脏再生疗法非常相关。在这里我们 将追求以下具体目标。具体目标1：利用亚微米3D打印制造基于ECM的 基于细胞外基质在天然心肌中分布的水凝胶生成等效性心肌组织 具有IPSC衍生的三系心肌细胞类型的增强功能。具体目标2：使用最近的 建立了T1-NOM P-31磁化饱和转移(MST)和2D化学位移成像(2D-CSI) 方法通过CK和ATPase检测心肌细胞的ATP流量是否发生了最严重的变化 梗死区的心内膜下层(Endo)。年下降的严重程度 心肌梗死后心肌内膜通过CK和ATPase产生ATP的能力与心肌梗死严重程度呈线性相关 左心室功能障碍。具体目标3：检查移植的功能是否有益于 利用人IPSC-CM、-内皮细胞(EC)和-SMC(SMC)构建新型ECM组织替代物 伴随着移植细胞对心肌的保留和整合增强，并与 降低室壁应力，进而通过以下两种途径改善心肌ATP生产储备 心肌梗死后心内膜CK和ATPase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.