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是 在过去的15年里，这是严格的科学讨论的主题。一些著名的 实验室已经表明，选定的成体干细胞/祖细胞来源可以 对大面积的梗死或化学损伤的心肌进行转分化和再填充 能够完全恢复心脏功能的新的心肌细胞。一个干细胞/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标记物(CD117)。然而，其他实验室还没有观察到选择的能力 当注射时，祖细胞或cKit+CPC通过转分化产生新的心肌细胞， 他们也没有观察到内源性干细胞可以明显产生新的心肌细胞。 消息来源。在过去的5年里，整个领域已经成为一件有争议的事情，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，我们在这里提出一种新的方法，即来自两个实验室的 每个营地将以盲目的方式合作，充分交换所有试剂和动物 用于生成共识数据的模型。此双PI应用程序还将几乎完全依赖于 老鼠遗传学和血统追踪的方法，以便更明确的数据将出现。这个 三个具体目标将解决首要假设，即注射外源 祖细胞进入心脏可通过旁分泌机制发挥心脏保护作用 行动。我们将不会讨论转分化假说，因为这似乎是 很大程度上是不可信的。旁分泌假说涉及新内皮细胞的生成。 来自内源性cKit+CpC和增强脑室及其周围的血流灌注 心肌梗死面积。它还可能涉及内源性心肌细胞的增强。 从现有的心肌细胞中增殖，保护交界区的心肌细胞免于凋亡 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 作为更大的“旁分泌假说”的一部分进行研究的高度结构化的实验 提出了一种用于生物样本之间的盲目交换的方法 这两个实验室。目标是完全基于更严格的数据来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。 这2名PI在与多个共享出版物合作方面有着长期的记录，并 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.