Innate immune response signaling in cardiac injury healing

摘要 由潜在的动脉粥样硬化引起的心肌梗死(MI)是主要疾病 在西方世界引发心力衰竭的后遗症。我们治疗这些疾病的能力 患者和他们的心力衰竭进展没有超过20%-30%的轻微延长 寿命在大约30年前通过基于神经内分泌的管理实现[1]。 需要新的治疗途径，其中最戏剧性的将是直接 产生新的心肌细胞以再生受损的心脏组织区域。 以前通过产生新的心肌细胞来再生心脏的尝试没有 尽管使用成体祖细胞进行了18年多的研究，但仍取得了成功。 然而，在啮齿动物模型中对心脏前体细胞的研究确实显示了一种功能 有益于心肌梗死受伤的心脏，尽管我们现在理解这不是由于 显著的新的心肌细胞的产生。相反，我们和其他人确定了一部小说 注射造血祖细胞对小鼠骨髓再生的作用机制 心肌梗死通过完善免疫反应损伤心脏。事实上，我们已经证明了 细胞疗法注射在最近因缺血而受损的心脏区域的侧翼- 再灌注(7天后)可优化愈合，减少梗塞面积扩大和 增强疤痕边界地带的物理特性(Vagnozzi等人，2020年，《自然》)。这些 有益的作用是通过选择性的巨噬细胞亚型活动在 心脏，强调免疫反应在心血管健康和 心肌梗死的愈合和代偿。在这里，我们提出了选择性与生俱来的假设 免疫反应信号通路和巨噬细胞亚型极化可 被用来帮助治愈心脏。我们更具体的假设是，治疗有一个 两者通过Toll样受体(TLR)信号传递的潜在保护成分 心肌细胞和巨噬细胞，这可以用来治疗极化 为了更好的愈合而产生的免疫反应。具体目标是：目标1，检查 心脏通过TLR信号传递先天免疫信号的机制。目标2，以 诱导性地改变心脏巨噬细胞亚型以重新编程先天免疫 细胞疗法的反应和愈合动力学。目的#3，确定成纤维细胞如何 心肌梗死后损伤心脏与巨噬细胞亚型的沟通影响愈合 细胞疗法的动力学。这类研究对于检验先天免疫系统如何 巨噬细胞和心肌细胞水平的信号影响心脏 炎性损伤反应，目的是改变这种反应，使心脏受益 在病人身上治愈。

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 [1]. 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 18 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, although we now understand that this is not due to significant new myocyte production. Instead we and others have identified a novel mechanism of benefit whereby injected progenitor cells have a rejuvenating effect on the MI-injured heart through refinement of the immune response. Indeed, we have shown that cell therapy injections that flank the recently injured area of the heart from ischemia- reperfusion (7 days later) 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 cardiovascular health and infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to help heal the heart. Our more specific hypothesis is that therapy has an underlying protective component through Toll-like receptor (TLR) signaling 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 examine the mechanism of innate immune signaling in the heart through TLR signaling. AIM #2, To inducibly alter macrophage subtypes in the heart to reprogram the innate immune response and healing dynamics by cell therapy. AIM #3, To determine how fibroblasts communicate with macrophage subtypes in the post-MI injured heart to affect healing dynamics by cell therapy. Such studies will be critical for examining how innate immune signaling at the level of macrophages and cardiomyocytes impacts the heart during an inflammatory injury response with the goal of modifying this response to benefit cardiac healing in patients.