Paracrine hypothesis underlying cardiac stem cell therapy

摘要 干细胞或祖细胞在促进心脏再生中所起的作用一直是 在过去的15年里，这是一个严谨的科学讨论话题。一些知名 实验室已经显示了数据，由此选择的成体干/祖细胞来源可以 转分化和重新填充大面积梗死或化学损伤的心肌， 新的心肌细胞完全恢复心室功能。一个干/祖细胞， 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标记物（CD117）。然而，其他实验室没有观察到选择的能力， 祖细胞或cKit + CPC，以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性干细胞产生新的心肌细胞 源在过去的5年里，整个领域已经成为一个有争议的问题， 截然相反的阵营，继续公布数据支持他们的原始 意见。因此，在这里，我们提出了一种新的方法， 每个营地将以盲法合作，充分交换所有试剂和动物。 模型来生成共识数据。这种双PI应用程序也将几乎完全依赖于 小鼠遗传学和谱系追踪方法，以便获得更明确的数据。的 三个具体目标将解决总体假设，即注入外源性 祖细胞进入心脏通过旁分泌机制产生心脏保护作用， 行动上我们将不讨论转分化假说，因为这似乎已经 基本上是不可信的旁分泌假说涉及新内皮细胞的产生 从内源性cKit + CPCs和增强心室灌注和周围的 心肌梗死面积。它也可能涉及增加内源性心肌细胞 从现有肌细胞增殖，保护肌细胞免于边缘区的凋亡 通过旁分泌因子和细胞外基质的保护性重塑，所有这些都将是 作为更大的"旁分泌假说"的一部分进行了研究。 提出了一种沿着系统的方法，用于在 2实验室我们的目标是生成一个决定性的数据集，完全基于更严格的 标准和方法，以期为心脏干细胞领域带来共识。 这两个PI在与多个共享出版物合作方面有着长期的记录， 联合赠款。

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.