Cell therapy regulates cardiac healing through innate immune response

摘要 由于动脉粥样硬化引起的心肌梗死（MI）是主要疾病 在西方世界导致心力衰竭的后遗症。我们治疗这些 患者和他们的心力衰竭没有进展超过轻度20-30%的扩展， 大约30年前通过基于神经内分泌的管理实现了寿命。新 需要治疗的途径，其中最引人注目的将是直接 产生新的心肌细胞以再生心脏组织的受损区域。 以前通过产生新的心肌细胞来再生心脏的尝试没有成功。 尽管使用成人祖细胞进行了超过15年的研究，但仍然取得了成功。 然而，在啮齿动物模型中对心脏祖细胞的研究确实显示了功能性的 有益于MI损伤的心脏，我们和其他人已经确定了一种新的机制， 细胞疗法的好处是通过改善免疫系统， 反应事实上，我们已经证明细胞疗法注射可以优化愈合， 减少梗死面积扩大，增加瘢痕边缘区物理性质 （Vageli等人，2020，Nature）。这些有益的影响是通过 选择性巨噬细胞亚型的活动在心脏，强调的重要性， 梗死愈合和补偿中免疫应答。这里我们提出假设 选择性先天免疫反应信号通路和巨噬细胞亚型 极化可以用来进一步治愈心肌梗死损伤，并解释细胞疗法是如何 在体内发挥作用。我们更具体的假设是，心肌梗死损伤或细胞治疗具有 通过cGAS-Sting在心肌细胞和 巨噬细胞，这可以在治疗上用来抑制免疫反应。 为了更好的愈合。具体目标是：目标#1，使用小鼠遗传学来识别 心脏中介导基于细胞疗法的心脏治疗的特定免疫细胞类型 心肌梗死后恢复活力目的#2，研究先天免疫的机制 通过cGAS-Sting在心脏中传递信号。目的#3，研究机制 由此细胞疗法使MI后受损的心脏恢复活力。这些研究将是至关重要的 研究巨噬细胞水平的先天免疫信号如何影响 心脏在炎症损伤反应期间或由于细胞治疗，目的是 改变这种反应以有利于患者的愈合。

Abstract Myocardial infarction (MI) due to underlying atherosclerosis is the leading disease sequela that precipitates heart failure in the Western world. Our ability to treat these patients and their heart failure has not progressed beyond a mild 20-30% extension in life span realized some 3 decades ago with neuroendocrine-based management. New therapeutic avenues are needed, the most dramatic of which would be directly generating new cardiomyocyte to regenerate the damaged area of heart tissue. Previous attempts to regenerate the heart through new myocyte production have not been successful despite more than 15 years of research using adult progenitor cells. However, studies with cardiac progenitor cells in rodent models did show a functional benefit to the MI-injured heart, and we and others have identified a novel mechanism of benefit whereby cell therapy has a rejuvenating effect through refinement of the immune response. Indeed, we have shown that cell therapy injections can optimize healing, reduce infarct area expansion and augment scar borderzone physical properties (Vagnozzi et al., 2020, Nature). These beneficial effects were mediated through selective macrophage subtype activity in the heart, underscoring the importance of the immune response in infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to further heal MI injury and to explain how cell therapy functions in vivo. Our more specific hypothesis is that MI injury or cell therapy has an underlying protective component through cGAS-Sting in both cardiomyocytes and macrophages, and this can be therapeutically exploited to polarize the immune response for better healing. The specific aims are: AIM #1, To use mouse genetics to identify the specific immune cell-types in the heart that mediate cell therapy-based cardiac rejuvenation post-MI injury. AIM #2, To examine the mechanism of innate immune signaling in the heart through cGAS-Sting. AIM #3, To investigate the mechanisms whereby cell therapy rejuvenates the post-MI injured heart. Such studies will be critical for examining how innate immune signaling at the level of macrophages impacts the heart during an inflammatory injury response or due to cell therapy with the goal of modifying this response to benefit healing in patients.