Investigation of a Right Ventricle Based Decellularized Extracellular Matrix Hydrogel and Cardiac Progenitor Cells as a Treatment for Right Ventricular Heart Failure

项目摘要 左冠状动脉发育不全综合征(HLHS)已成为最具破坏性的先天性心脏病之一。 患有HLHS的患者左侧心脏发育不全且功能不全，需要一系列 姑息性干预以纠正疾病，并使患者利用右室(RV)作为他们的 主体泵。虽然姑息疗法降低了患者的死亡率，但它仍然不是治愈的方法。因为 在患者的一生中，RV将面临的全身压力和容量过载，即负RV 重塑可能发生，并最终导致心力衰竭。负性RV重塑也可呈现许多 与左心室(LV)负向重构相同的特征，包括肥厚和间质 纤维化症。一种可注射的猪左室脱细胞心肌基质水凝胶 心肌已被证明可以逆转左心室负向重构，改善心功能。 大动物心肌梗死模型。此外，研究表明，心脏祖细胞的交付 细胞(CPC)对受损的心室有促进心脏修复的作用。对个人和个人的调查 基于RV的心肌基质水凝胶和CPC的组合特性作为Right潜在的治疗方法 室性心力衰竭是有根据的。假设如下：MM水凝胶作为输送平台 对于CPC将通过促进健康的心脏代谢，减少纤维化来改善RV功能 在HLHS大鼠肺动脉带(PAB)模型中预防心肌肥厚 而不是单独使用任何一个组件。这一假说将通过以下目标进行调查。目标1：实现 建立和鉴定轮状病毒来源的MM水凝胶，并评估其在存活、血管生成和纤维化方面的变化 MM包裹大鼠成纤维细胞的基因表达及血管生成旁分泌信号。目标2：评估 MM水凝胶与大鼠CPC联合治疗的疗效及联合作用机制的探讨 MM水凝胶和大鼠CPC对大鼠PAB模型相关细胞群的治疗作用。 RV衍生MM水凝胶的制备、表征及其对CPC的影响 行为将阐明RV MM是否具有治疗潜力。论证了组合算法的有效性 MM/CPC疗法在HLHS姑息治疗后RVHF模型中的应用，也将证明进一步研究该疗法对 用于治疗因其他情况而衰竭的RV，如肺动脉高压。 了解联合疗法或其任何一种成分单独作用的作用机制 细胞类型，将阐明未来设计心血管再生疗法的重要目标。

Project Summary Hypoplastic Left Syndrome (HLHS) has grown to be one of the most devastating congenital heart defects. Patients born with HLHS have an underdeveloped and dysfunctional left side of the heart and require a series of palliative interventions to correct the disorder and leave the patient utilizing their right ventricle (RV) as their main systemic pump. While palliation reduces the mortality of patients, it is still not a cure. Because of the systemic pressures and volume overload that the RV will now face over the patient’s lifetime, negative RV remodeling may occur and ultimately lead to heart failure. Negative RV remodeling can also present many of the same features that are seen in negative left ventricle (LV) remodeling, including hypertrophy and interstitial fibrosis. An injectable decellularized myocardial matrix hydrogel (MM) derived from porcine left ventricular myocardium has been shown to reverse negative LV remodeling and improved cardiac function in small and large animal myocardial infarction models. Additionally, it has been shown that the delivery of cardiac progenitor cells (CPCs) to the injured ventricle can enhance cardiac repair. The investigation of the individual and combinatorial properties of a RV based myocardial matrix hydrogel and CPCs as a potential therapy for right ventricular heart failure is warranted. The hypothesis is as follows: A MM hydrogel as a delivery platform for CPCs will lead to improved RV function via promoting healthy cardiac metabolism, reducing fibrosis in the infarct, and preventing cardiac hypertrophy in a rat pulmonary artery band (PAB) model for HLHS as opposed to either component alone. The hypothesis will be investigated via the following aims. Aim 1: To develop and characterize a RV derived MM hydrogel and assess the changes in survival, angiogenic and fibrosis gene expression and angiogenic paracrine signaling of MM encapsulated rat CPCs. Aim 2: To evaluate the efficacy of a combined therapy of MM hydrogel and rat CPCs and determine mechanism of action of a combined therapy of MM hydrogel and rat CPCs on relevant cell populations in a rat PAB model. The fabrication and characterization of an RV derived MM hydrogel and assessing its influence on CPC behavior will elucidate if the RV MM has therapeutic potential. Demonstrating the efficacy of the combinatorial MM/CPC therapy in a model of RVHF after HLHS palliation, will also justify further study into the therapy for usage to treat the failing RV because of other conditions, such as pulmonary arterial hypertension. Understanding the mechanism of action of the combinatorial therapy or either of its components alone on key cell types, will explicate important targets for the future of designing cardiovascular regenerative therapies.