Enhanced Myocardial Repair with CardioClusters and CardioChimeras

利用 CardioClusters 和 CardioChimeras 增强心肌修复

• 批准号: 8675146
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 37.38万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675146
• 关键词: Acute myocardial infarction; Adoptive Transfer; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autologous; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Death; Cell Differentiation process; Cell Line; Cell Proliferation; Cell Survival; Cell Therapy; Cell fusion; Cells; Characteristics; Cicatrix; Clinical; Clinical Trials; Coculture Techniques; Commit; Communication; Disease; Engineering; Engraftment; Exhibits; Extracellular Matrix Proteins; Failure; Genetic Materials; Goals; Growth; Growth Factor; Healthcare Systems; Heart; Heart Diseases; Heart failure; Human; Hybrids; Hypoxia; Individual; Inflammation; Injection of therapeutic agent; Injury; Knowledge; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Meta-Analysis; Methods; Monitor; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Output; Patients; Pattern; Population; Prevention; Property; Public Health; Relative (related person); Safety; Smooth Muscle Myocytes; Solutions; Stem cells; Stimulus; Structure; Suspension substance; Suspensions; Testing; Tissues; United States; angiogenesis; base; cardiac repair; cell behavior; cell growth; cell type; clinically relevant; combinatorial; cytokine; falls; human stem cells; improved; innovation; insight; mortality; muscular structure; novel; paracrine; public health relevance; regenerative; repaired; restoration; stem; stem cell population

DESCRIPTION (provided by applicant): Regenerative capacity of the heart is mediated through multiple distinct populations of stem cell types that are the subject of ongoing intense study. In the past decade, isolation and characterization of cardiac progenitor cells (CPCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) has provided substantial insight to the capabilities of stem cells to rebuild the damaged heart and advance clinical therapy. Clinical trials have proven the efficacy and safety of autologous and allogeneic CPC and MSC delivery to human patients, yet improvements in cardiac function and reduction in scar tissue remain modest and far below that needed for restoration of normal functional output. This proposal overcomes these current cell- based limitations with two novel methods for improving myocardial repair: 1) CardioClusters, a three- dimensional microenvironment consisting of CPCs, MSCs and EPCs, and 2) CardioChimeras, the product of cellular fusion between two stem cell populations. The innovation of this proposal is the creation of CardioClusters and CardioChimeras with the ability to capitalize upon beneficial attributes of multiple human stem cells from a single patient providing a clinically relevant translational strategy. The short-term goal of this proposal will determine the enhanced proliferation, growth, survival and commitment potential of CardioChimeras and stem cells in CardioClusters, which are optimized for improving cell-based therapy. Accomplishing the stated aims of this proposal will yield the construction and comprehensive characterization of CardioClusters and CardioChimeras. Specific Aims are: 1) CardioClusters exhibit enhanced proliferation, survival and cardiac commitment relative to cardiospheres, single or combinatorial cell populations, 2) CardioChimeras display improved characteristics of growth, survival, secretion of paracrine factors and cardiac commitment relative to non-fused cell populations and 3) CardioClusters as well as CardioChimeras restore myocardial structure and function after intramyocardial injection better than cardiospheres or single / multiple cell suspensions. The significance of these studies is to create novel cell-based strategies engineered to improve current cellular therapy to mitigate ischemic disease. Collectively, studies in this proposal will pave the way for interventional approaches to selectively adapt stem cell behavior and merge beneficial attributes of stem cell populations found within the human heart for prevention of heart failure after cardiomyopathic injury.

描述（由申请人提供）：心脏的再生能力是通过多种不同的干细胞类型群体介导的，这些干细胞类型是正在进行的深入研究的主题。在过去的十年中，心脏祖细胞（CPC）、间充质干细胞（MSC）和内皮祖细胞（EPC）的分离和表征为干细胞重建受损心脏和推进临床治疗的能力提供了深入的见解。临床试验已证明向人类患者输送自体和同种异体 CPC 和 MSC 的有效性和安全性，但心脏功能的改善和疤痕组织的减少仍然有限，远低于恢复正常功能输出所需的水平。该提案通过两种改善心肌修复的新方法克服了当前基于细胞的局限性：1）CardioClusters，由 CPC、MSC 和 EPC 组成的三维微环境；2）CardioChimeras，两个干细胞群之间细胞融合的产物。该提案的创新之处在于创建了 CardioClusters 和 CardioChimeras，能够利用单个患者的多个人类干细胞的有益属性，提供临床相关的转化策略。该提案的短期目标将确定 CardioChimeras 和 CardioClusters 中干细胞的增殖、生长、存活和承诺潜力的增强，这些细胞经过优化以改善基于细胞的治疗。实现该提案的既定目标将产生 CardioClusters 和 CardioChimeras 的构建和全面表征。具体目标是：1) 相对于心脏球、单个或组合细胞群，CardioClusters 表现出增强的增殖、存活和心脏承诺，2) 相对于非融合细胞群，CardioChimeras 表现出改善的生长、存活、旁分泌因子分泌和心脏承诺特征3) CardioClusters 以及 CardioChimeras 在心肌内注射后比心脏球或单/多细胞悬浮液更好地恢复心肌结构和功能。这些研究的意义在于创建新的基于细胞的策略，旨在改善当前的细胞疗法以减轻缺血性疾病。总的来说，该提案中的研究将为介入方法铺平道路，以选择性地适应干细胞行为并融合人类心脏内发现的干细胞群的有益属性，以预防心肌病损伤后的心力衰竭。