Enhanced Myocardial Repair with CardioClusters and CardioChimeras

利用 CardioClusters 和 CardioChimeras 增强心肌修复

• 批准号: 9266810
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266810
• 关键词: Acute myocardial infarction; Adoptive Transfer; Allogenic; Alpha Cell; 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; Communication; Dimensions; Disease; Engineering; Engraftment; Exhibits; Extracellular Matrix Proteins; Failure; Genetic Materials; Genotype; Goals; Growth; Growth Factor; Healthcare Systems; Heart; Heart Diseases; Heart failure; Human; Hybrids; Hypoxia; Individual; Inflammation; Injectable; Injection of therapeutic agent; Injury; Intervention; Knowledge; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Meta-Analysis; Methods; Monitor; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Output; Patients; Pattern; Phenotype; Population; Prevention; Property; Public Health; Recruitment Activity; Safety; Stem cells; Stimulus; Structure; Suspensions; Testing; Tissues; United States; Vascular Smooth Muscle; 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; phenotypic biomarker; public health relevance; regenerative; repaired; restoration; stem cell population; translational approach

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种群介导的，这些干细胞类型是正在进行的激烈研究的主题。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的心脏的能力提供了实质性的见解。临床试验证明了自体和同种异体CPC以及MSC递送对人类患者的疗效和安全性，但心脏功能的改善和疤痕组织的减少仍然适度，远低于恢复正常功能输出所需的。该建议通过两种改善心肌修复的新方法克服了这些当前基于细胞的局限性：1）心脏群体，由CPC，MSC和EPC组成的三维微环境以及2）心脏chimeras，两种干细胞群之间的细胞融合的产物。该提案的创新是创建心脏群体和心脏chimer虫，能够从单个患者提供临床相关的翻译策略的多个人类干细胞的有益属性。该提案的短期目标将确定心脏群体中心脏chimeras和干细胞的增殖，生长，生存和承诺潜力的增强，这是对改善基于细胞的治疗的优化。完成该提案的既定目标将产生心脏群体和心脏奇马群的构建和全面表征。具体目的是：1）心脏群体相对于心脏球群，单个或组合细胞种群的增殖，生存和心脏承诺增强，2）心脏chimeras的生长，旁分泌因素和与非脉络细胞种群相对的生存，分泌因素和心脏承诺的分泌的特征提高心脏内注射比心圈或单个 /多个细胞悬浮液更好。这些研究的意义是创建设计出设计的新型基于细胞的策略，以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的方法铺平道路，以选择性地适应干细胞行为并合并人心中发现的干细胞种群的有益属性，以预防心肌病后心力衰竭。