Enhanced Myocardial Repair with CardioClusters and CardioChimeras

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（CPCs）、间充质干细胞（MSCs）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输送给人类患者的有效性和安全性，但心功能的改善和疤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水平。本研究提出了两种改善心肌修复的新方法，克服了目前基于细胞的局限性：1)CardioClusters，一种由心肌干细胞、间充质干细胞和EPCs组成的三维微环境；2)CardioChimeras，两种干细胞群体之间细胞融合的产物。这一提议的创新之处在于心脏集群和心脏嵌合体的创造，它们能够利用来自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心脏嵌合体和干细胞在心脏簇中的增殖、生长、存活和承诺潜力，这些都是优化的，可以改善细胞治疗。完成本提案的既定目标将产生心脏簇和心脏嵌合体的构建和全面表征。具体目标是：1)与心球细胞、单个或组合细胞群相比，心细胞簇具有更强的增殖、存活和心脏承受力；2)心嵌合体具有更好的生长、存活、与非融合细胞群和3)心肌内注射相比，心肌球或单/多细胞悬浮液能更好地恢复心肌结构和功能。这些研究的意义在于创造新的基于细胞的策略，以改进当前的细胞治疗来减轻缺血性疾病。总的来说，本提案中的研究将为选择性适应干细胞行为的介入方法铺平道路，并合并人类心脏中发现的干细胞群体的有益属性，以预防心肌病损伤后的心力衰竭。

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.