Cardiac Regeneration with Bioengineered Human Stem Cells

利用生物工程人类干细胞进行心脏再生

• 批准号: 9123170
• 负责人: Young-Sup Yoon
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123170
• 关键词: Affect; Alabama; Antibodies; Autologous; Biocompatible Materials; Biomedical Engineering; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Maturation; Cell Survival; Cell Therapy; Cell Transplants; Cells; Choristoma; Defect; Disease; Echocardiography; Endothelial Cells; Engineering; Engraftment; Ethics; Extracellular Matrix; Fibroblasts; Functional disorder; Gel; Genes; Goals; Growth; Heart; Heart failure; Human; Human Engineering; Image; Immunologics; In Vitro; Laboratories; Magnetic Resonance Imaging; Messenger RNA; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myosin Heavy Chains; Peptides; Pluripotent Stem Cells; Population; Population Heterogeneity; Protocols documentation; Publishing; Research Personnel; Risk; Role; Source; Specificity; Stem cells; Supporting Cell; Techniques; Technology; Teratoma; Therapeutic Effect; Therapeutic Uses; Transplantation; Tumor Tissue; Undifferentiated; United States; Universities; Vascularization; Ventricular; Ventricular Function; Virus; Work; base; cardiac regeneration; cardiac repair; cell behavior; cell type; cellular engineering; clinical application; embryonic stem cell; expectation; human embryonic stem cell; human stem cells; induced pluripotent stem cell; injured; insight; microCT; mortality; nanoscale; nanostructured; new technology; novel; novel strategies; peptidomimetics; public health relevance; repaired; research study; stem cell therapy

 DESCRIPTION (provided by applicant): Human pluripotent stem cells (hPSCs), which include embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), offer unprecedented promise for cardiac repair; however, many hurdles must be overcome before clinical application is possible. Current methods for differentiating cardiomyocytes (CMs) from hPSCs result in heterogeneous populations of cells, including undifferentiated or non-CM cells, which may pose a risk for tumor or aberrant tissue formation. For therapeutic use, ventricular CMs (vCMs) are ideal because vCMs are the most extensively affected cell type in myocardial infarction and the major source for generating cardiac contractile forces. Although various strategies have been attempted for CM enrichment, these strategies have drawbacks in terms of purity or specificity. We recently developed a novel technology to purify CMs by targeting CM-specific intracellular mRNAs using molecular beacons (MBs), which will enable isolation of the desired CMs for use in therapy. Another obstacle to cell therapy is low retention of transplanted cells in injured myocardium. To overcome this problem, engineering of CMs with biomaterials or co-transplantation with other cells has been attempted. My co-investigator and I have been working to develop technologies for engineering cardiovascular cells with peptide amphiphile (PA)-based nanostructured biomaterials for enhancing the effects of cell therapy. The goal of this proposal is to develop a strategy for cardiac repair with hPSC-derived vCMs by two novel approaches: to purify hPSC-derived vCMs with MBs and to engineer these CMs with self-assembled nanomatrix gels and other cells including hPSC-derived ECs and fibroblasts. In aim 1, we seek to purify vCMs from differentiating hPSCs using specific MBs. In aim 2, we will engineer purified hPSC-derived CMs, hPSC-derived ECs and other supportive cells with extracellular matrix-mimicking self-assembled nanomatrix gel which contains growth factors to enhance cell viability, vascularization, and cell maturation, and determine the optimal cell- nanomatrix constructs. In aim 3, we will determine the therapeutic effects of engineered hPSC- derived cardiovascular cell constructs on injured myocardium and elucidate the underlying mechanisms. We anticipate that the results of the proposed experiments will yield new insight into the role of novel stem cell therapy for cardiac repair.

 描述（由申请人提供）：人类多能干细胞（hPSC），包括胚胎干细胞（hESC）和诱导多能干细胞（hiPSC），为心脏修复提供了前所未有的前景;然而，在临床应用之前必须克服许多障碍。目前用于从hPSC分化心肌细胞（CM）的方法导致细胞的异质群体，包括未分化或非CM细胞，这可能造成肿瘤或异常组织形成的风险。对于治疗用途，心室CM（vCM）是理想的，因为vCM是心肌梗死中受影响最广泛的细胞类型，并且是产生心脏收缩力的主要来源。尽管已经尝试了各种策略用于CM富集，但是这些策略在纯度或特异性方面具有缺点。我们最近开发了一种新的技术，通过使用分子信标（MB）靶向CM特异性细胞内mRNA来纯化CM，这将使得能够分离所需的CM用于治疗。细胞治疗的另一个障碍是移植细胞在受损心肌中的低保留。为了克服这个问题，已经尝试了用生物材料工程化CM或与其他细胞共移植。我的合作研究者和我一直在努力开发技术，用基于肽两亲物（PA）的纳米结构生物材料来工程化心血管细胞，以增强细胞治疗的效果。该提案的目标是通过两种新方法开发用hPSC衍生的vCM进行心脏修复的策略：用MB纯化hPSC衍生的vCM，并用自组装纳米基质凝胶和其他细胞（包括hPSC衍生的EC和成纤维细胞）工程化这些CM。在目的1中，我们寻求使用特异性MB从分化中的hPSC纯化vCM。在目标2中，我们将用含有生长因子的细胞外基质模拟自组装纳米基质凝胶工程化纯化的hPSC衍生的CM、hPSC衍生的EC和其他支持细胞，以增强细胞活力、血管形成和细胞成熟，并确定最佳的细胞-纳米基质构建体。在目标3中，我们将确定工程化的hPSC衍生的心血管细胞构建体对损伤的心肌的治疗效果并阐明潜在的机制。我们预计，拟议的实验结果将产生新的见解的作用，新的干细胞治疗心脏修复。