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.

项目摘要 左室发育不良综合征（HLHS）已发展成为最具破坏性的先天性心脏病之一。 先天性HLHS患者的左心室发育不全且功能障碍， 姑息性干预措施，以纠正疾病，并离开病人利用他们的右心室（RV）作为他们的 主系统泵虽然姑息治疗降低了患者的死亡率，但它仍然不是治愈方法。因为 RV在患者一生中将面临的全身压力和容量超负荷，负RV 可能发生重塑并最终导致心力衰竭。负性右心室重塑也可以表现出许多 与阴性左心室（LV）重塑中观察到的特征相同，包括肥大和间质性 纤维化一种可注射的猪左心室脱细胞心肌基质水凝胶 心肌已经显示出逆转负性LV重构和改善小和 大动物心肌梗死模型。此外，已经表明，心脏祖细胞的递送 细胞（CPC）到受损的心室可以增强心脏修复。对个人的调查， 基于RV的心肌基质水凝胶和CPC的组合特性作为右心室的潜在疗法 心室性心力衰竭是有根据的假设如下：MM水凝胶作为递送平台 将通过促进健康的心脏代谢，减少纤维化， 在HLHS的大鼠肺动脉带（PAB）模型中， 而不是单独的任一组分。该假设将通过以下目的进行研究。目标1： 开发和表征RV衍生的MM水凝胶，并评估存活率、血管生成和纤维化的变化 MM包裹的大鼠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联合治疗功效和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衍生的MM水凝胶的制备和表征及其对CPC的影响 行为将阐明RV MM是否具有治疗潜力。展示了组合的功效 在HLHS缓解后的RVHF模型中进行MM/CPC治疗，也将证明进一步研究治疗 用于治疗因其他疾病（如肺动脉高压）导致的RV衰竭。 了解联合治疗或其任何一种成分单独治疗的作用机制， 细胞类型，将阐明未来设计心血管再生疗法的重要目标。