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 干细胞或祖细胞在促进心脏再生中发挥的作用一直被认为是 过去15年来严格科学讨论的话题。一批杰出的 实验室已显示数据表明，选定的成体干细胞/祖细胞来源可以 转分化并重新填充大面积的梗塞或化学损伤的心肌 完全恢复心室功能的新心肌细胞。一种干细胞/祖细胞具有 被高度吹捧为真正的心脏再生细胞类型的是表达细胞表面 cKit 标记（CD117）。然而，其他实验室尚未观察到选择的能力 祖细胞或 cKit+ CPC 在注射时通过转分化产生新的肌细胞， 他们也没有观察到内源干细胞产生明显的新肌细胞 来源。在过去的 5 年里，整个领域已经成为一个有争议的话题，基本上有 2 截然相反的阵营继续发布支持其原始数据的数据 观察。因此，我们在这里提出了一种新颖的方法，来自 2 个实验室 每个营地将以盲法方式合作，充分交换所有试剂和动物 模型来生成共识数据。这种双 PI 应用程序还将几乎完全依赖于 小鼠遗传学和谱系追踪方法，以便产生更明确的数据。这 三个具体目标将解决注射外源性的总体假设 祖细胞进入心脏通过旁分泌机制产生心脏保护作用 行动。我们不会讨论转分化假说，因为这似乎是 很大程度上失去了信誉。旁分泌假说涉及新内皮细胞的产生 来自内源性 cKit+ CPC 以及心室及其周围心室灌注的增强 心肌梗塞面积。它还可能涉及内源性肌细胞的增强 现有心肌细胞的增殖，保护边界区心肌细胞免于凋亡 通过旁分泌因子和细胞外基质的保护性重塑，所有这些都将被 作为更大的“旁分泌假说”的一部分进行了高度结构化的实验 提出了一种方法以及一种用于生物样本盲交换的系统 2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，希望为心脏干细胞领域带来共识。 两位 PI 有着与多个共享出版物合作的长期记录， 联合赠款。