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个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密集研究的主题。在过去的十年里，心脏祖细胞（CPC）、间充质干细胞（MSC）和内皮祖细胞（EPCs）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实质性的见解。临床试验已经证明了自体和同种异体CPC和MSC递送到人类患者的有效性和安全性，但心脏功能的改善和瘢痕组织的减少仍然是适度的，远远低于恢复正常功能输出所需的。该提议用两种用于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）β-簇，一种由CPC、MSC和EPC组成的三维微环境，和2）β-嵌合体，两种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具有利用来自单个患者的多个人类干细胞的有益属性的能力的多个簇和多个嵌合体，从而提供临床相关的翻译策略。该提案的短期目标将确定增强的增殖，生长，存活和承诺潜力的嵌合体和干细胞在细胞群，这是优化，以改善基于细胞的治疗。实现这一建议的既定目标将产生的建设和全面表征的CNOs集群和CNOs嵌合体。具体目标是：1）相对于心脏球、单个或组合细胞群，β-淀粉样蛋白簇表现出增强的增殖、存活和心脏定型，与非融合细胞群相比，旁分泌因子的分泌和心脏定型，以及3）心肌内注射后，与心脏球或单一/多种细胞悬液。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治疗以减轻缺血性疾病。总的来说，这项提案中的研究将为干预方法铺平道路，以选择性地适应干细胞行为，并合并人类心脏中发现的干细胞群体的有益属性，以预防心肌损伤后的心力衰竭。