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

基于右心室的脱细胞细胞外基质水凝胶和心脏祖细胞治疗右心室心力衰竭的研究

• 批准号: 10705000
• 负责人: Jervaughn D Hunter
• 金额: $ 2.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705000
• 关键词: Adverse event; Animals; Aorta; Apoptosis; Behavior; Biochemical; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Therapy; Cells; Combined Modality Therapy; Congenital Heart Defects; Custom; Defect; Disease; Echocardiography; Encapsulated; Enzyme-Linked Immunosorbent Assay; Euthanasia; Extracellular Matrix; FDA approved; Face; Family suidae; Fibroblasts; Fibrosis; Future; Gene Expression; Goals; Harvest; Heart; Heart Hypertrophy; Heart Transplantation; Heart failure; Histology; Hydrogels; Hypertrophy; Hypoplastic Left Heart Syndrome; Immune; Immunohistochemistry; In Vitro; Individual; Infarction; Inflammation; Inflammatory Response; Injectable; Injections; Injury; Intervention; Investigation; Label; Left; Left Ventricular Remodeling; Left ventricular structure; Magnetic Resonance Imaging; Measures; Metabolism; Modeling; Monitor; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Newborn Infant; Paracrine Communication; Patients; Population; Property; Property Rights; Pulmonary artery structure; Pump; Randomized; Rattus; Respiration; Right ventricular structure; Saline; Series; Side; Sprague-Dawley Rats; Therapeutic; Time; Tissue-Specific Gene Expression; Tube; Vascular Endothelial Cell; Ventricular; angiogenesis; cardiac repair; cell behavior; cell type; combinatorial; design; efficacy evaluation; efficacy study; fabrication; fatty acid oxidation; heart function; heart metabolism; improved; inflammatory modulation; injured; interstitial; mortality; nano-string; neovascularization; palliation; palliative; pediatric patients; physical property; preservation; pressure; prevent; pulmonary arterial hypertension; regenerative therapy; repaired; right ventricular failure; right ventricular remodeling; standard care; stem cell survival; stem cells

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.

项目概要 左侧发育不良综合征 (HLHS) 已成为最具破坏性的先天性心脏病之一。 出生时患有 HLHS 的患者左侧心脏发育不全且功能障碍，需要进行一系列的治疗 姑息性干预措施来纠正疾病并使患者利用右心室（RV）作为他们的 主要系统泵。虽然姑息治疗可以降低患者的死亡率，但它仍然不是治愈方法。因为 右心室在患者一生中将面临的全身压力和容量超负荷，负右心室 可能会发生重构并最终导致心力衰竭。负向 RV 改造还可以呈现许多 与负性左心室 (LV) 重塑相同的特征，包括肥厚和间质 纤维化。一种源自猪左心室的可注射脱细胞心肌基质水凝胶（MM） 心肌已被证明可以逆转负性左心室重构并改善小型和小型患者的心功能。 大型动物心肌梗死模型。此外，已经表明心脏祖细胞的输送 细胞（CPC）转移到受伤的心室可以增强心脏修复。对个人和 基于 RV 的心肌基质水凝胶和 CPC 的组合特性作为右旋肉瘤的潜在疗法 室性心力衰竭是必要的。假设如下：MM水凝胶作为递送平台 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 HLHS 大鼠肺动脉带 (PAB) 模型中的梗塞并预防心脏肥大 而不是单独使用任一组件。该假设将通过以下目标进行研究。目标 1： 开发和表征 RV 衍生的 MM 水凝胶，并评估存活、血管生成和纤维化的变化 MM 封装的大鼠 CPC 的基因表达和血管生成旁分泌信号传导。目标 2：评估 MM水凝胶和大鼠CPC联合治疗的功效并确定联合治疗的作用机制 MM 水凝胶和大鼠 CPC 对大鼠 PAB 模型中相关细胞群的治疗。 RV 衍生 MM 水凝胶的制备和表征以及评估其对 CPC 的影响 行为将阐明 RV MM 是否具有治疗潜力。证明组合的有效性 HLHS 姑息治疗后 RVHF 模型中的 MM/CPC 治疗也将证明进一步研究该疗法的合理性 用于治疗因其他疾病（例如肺动脉高压）而导致的右心室衰竭。 了解组合疗法或其任一成分单独的作用机制 细胞类型，将为未来设计心血管再生疗法阐明重要目标。