Paracrine hypothesis underlying cardiac stem cell therapy

心脏干细胞治疗的旁分泌假说

• 批准号: 9313922
• 负责人: Steven R Houser
• 金额: $ 77.11万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313922
• 关键词: ABCG2 gene; Address; Adult; Affect; Agreement; Alleles; Animal Model; Antigens; Apoptosis; Area; Basic Science; Biochemical; Biology; Blinded; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; C-KIT Gene; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell surface; Cells; Chemicals; Clinical Data; Clinical Trials; Conflict (Psychology); Consensus; Data; Data Set; Endothelial Cells; Extracellular Matrix; GATA4 gene; Generations; Genes; Genetic; Goals; Grant; Heart; Hematopoietic stem cells; Human; Immune response; Immunosuppression; Infarction; Inflammatory; Injectable; Injection of therapeutic agent; Injury; Investigation; Joints; Journals; Knock-in Mouse; Laboratories; Literature; Mediating; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Outcome; Paper; Patients; Perfusion; Plant Roots; Play; Population; Production; Proto-Oncogene Protein c-kit; Publications; Publishing; Reagent; Regenerative response; Reporting; Research Personnel; Role; Sampling; Scientist; Side; Source; Stem cells; Structure; System; Testing; Time; Tissues; Ventricular; Ventricular Function; Work; adult stem cell; base; cardiac regeneration; cell type; genetically modified cells; injured; novel strategies; paracrine; progenitor; protective effect; regenerative; repaired; stem; stem cell therapy; transcription factor; transdifferentiation

Abstract The role that stem or progenitor cells play in promoting cardiac regeneration has been the topic of rigorous scientific discussion over the past 15 years. A number of prominent laboratories have shown data whereby select sources of adult stem/progenitor cells can transdifferentiate and repopulate large areas of infarction or chemically injured myocardium with new cardiomyocytes that fully restore ventricular function. One stem/progenitor cell that has been highly touted as a true cardiac regenerative cell type is that expressing the cell surface marker for cKit (CD117). However, other laboratories have not observed the ability of select progenitors cells or cKit+ CPCs to generate new myocytes by transdifferentiation when injected, nor did they observe appreciable generation of new myocytes from endogenous stem cell sources. The entire field has become a contentious affair these past 5 years with essentially 2 diametrically opposed camps that continue to publish data supportive of their original observations. Hence, here we are proposing a novel approach whereby 2 laboratories from each camp will work together in a blinded manner with full exchange of all reagents and animal models to generate consensus data. This dual-PI application will also rely almost exclusively on mouse genetics and lineage tracing approaches so that more definitive data will arise. The three specific aims will address the overarching hypothesis that injection of exogenous progenitor cells into the heart results in cardioprotection through a paracrine mechanism of action. We will not address the transdifferentiation hypothesis as this seems to have been largely discredited. The paracrine hypothesis involves the generation of new endothelial cells from endogenesis cKit+ CPCs and the enhancement of ventricular perfusion in and around the area of myocardial infarction. It also may involve the augmentation of endogenous myocyte proliferation from existing myocytes, protection of myocytes from apoptosis in the border zone by paracrine factors and protective remodeling of the extracellular matrix, all of which will be investigated as part of the larger “paracrine hypothesis” A highly structured experimental approach is proposed along with a system for blinded exchanges of biologic samples between the 2 laboratories. The goal is to generate a decisive data set based entirely on more rigorous standards and approaches, with the hope of bringing consensus to the cardiac stem cell field. The 2 PIs have a long track record of working together with multiple shared publications and joint grants.

抽象的 茎或祖细胞在促进心脏再生中所起的作用是 在过去15年中，严格的科学讨论主题。许多突出的 实验室已经显示了数据，从而选择成人茎/祖细胞的来源可以 转分化和重新填充大面积梗塞或化学受伤的心肌 完全恢复心室功能的新心肌细胞。一个茎/祖细胞 被高度吹捧为真正的心脏再生细胞类型是表达细胞表面 CKIT的标记（CD117）。但是，其他实验室尚未观察到选择的能力 祖细胞或ckit+ cpcs在注射时通过转分化生成新的肌细​​胞， 他们也没有观察到内源性干细胞的新肌细胞的欣赏 来源。在过去的5年中，整个领域已经成为一个有争议的事情，本质上是2 截然相反的营地继续发布数据支持其原始的数据 观察。因此，在这里我们提出了一种新颖的方法，其中2个实验室来自 每个营地将以盲目的方式一起工作，并完全交换所有试剂和动物 生成共识数据的模型。该双PI应用程序也将几乎完全依赖 小鼠遗传学和谱系追踪方法将出现更确定的数据。 三个具体目标将解决注入外源的总体假设 祖细胞进入心脏 行动。我们不会解决转变假设，因为这似乎是 在很大程度上被抹黑。旁分泌假设涉及新的内皮细胞的产生 从内生元素CKIT+ CPCS以及室内和周围的心室灌注的增强 心肌梗塞的区域。它也可能涉及内源性心肌细胞的增强 现有肌细胞的扩散，保护肌细胞免受边界区域的凋亡 通过旁分泌因子并保护细胞外基质的重塑，所有这些都将是 作为较大的“旁分泌假说”的一部分进行了研究 提出了方法以及用于在生物样品之间盲目交换的系统 两个实验室。目标是完全基于更严格的数据集生成决定性的数据集 标准和方法，希望将共识带入心脏干细胞场。 这2个PI与多个共享出版物一起工作有很长的记录， 关节补助。