Department of Bioengineering, University of California, San Diego, La Jolla, California.
Sanford Consortium for Regenerative Medicine, La Jolla, California.
Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2211-H2221. doi: 10.1152/ajpheart.00056.2021. Epub 2021 Mar 26.
Aside from the first week postnatal, murine heart regeneration is restricted and responses to damage follow classic fibrotic remodeling. Recent transcriptomic analyses have suggested that significant cross talk with the sterile immune response could maintain a more embryonic-like signaling network that promotes acute, transient responses. However, with age, this response-likely mediated by neonatal yolk sac macrophages-then transitions to classical macrophage-mediated, cardiac fibroblast (CF)-based remodeling of the extracellular matrix (ECM) after myocardial infarction (MI). The molecular mechanisms that govern the change with age and drive fibrosis via inflammation are poorly understood. Using multiple ribonucleic acid sequencing (RNA-Seq) datasets, we attempt to resolve the relative contributions of CFs and macrophages in the bulk-healing response of regenerative () and nonregenerative hearts (+). We performed an analysis of bulk RNA-Seq datasets from myocardium and cardiac fibroblasts as well as a single-cell RNA-Seq dataset from cardiac macrophages. MI-specific pathway differences revealed that nonregenerative hearts generated more ECM and had larger matricellular responses correlating with inflammation, produced greater chemotactic gradients to recruit macrophages, and expressed receptors for danger-associated molecular patterns at higher levels than neonates. These changes could result in elevated stress-response pathways compared with neonates, converging at NF-κB and activator protein-1 (AP-1) signaling. Profibrotic gene programs, which greatly diverge on post MI, lay the foundation for chronic fibrosis, and thus postnatal hearts older than 7 days typically exhibit significantly less regeneration. Our analyses suggest that the macrophage ontogenetic shift in the heart postnatally could result in detrimental stress signaling that suppresses regeneration. Immediately postnatal mammalian hearts are able to regenerate after infarction, but the cells, pathways, and molecules that regulate this behavior are unclear. By comparing RNA-Seq datasets from regenerative mouse hearts and older, nonregenerative hearts, we are able to identify biological processes that are hallmarks of regeneration. We find that sterile inflammatory processes are upregulated in nonregenerative hearts, initiating profibrotic gene programs 3 days after myocardial infarction that can cause myocardial disease.
除了产后第一周外，鼠类心脏的再生受到限制，损伤后的反应遵循经典的纤维化重塑过程。最近的转录组分析表明，与无菌免疫反应的显著交叉对话可以维持更具胚胎样信号网络，促进急性、短暂的反应。然而，随着年龄的增长，这种反应——可能由新生蛋黄囊巨噬细胞介导——随后转变为经典的巨噬细胞介导的、心肌梗死后心脏成纤维细胞（CF）对细胞外基质（ECM）的重塑。调控这种随年龄变化并通过炎症导致纤维化的分子机制尚不清楚。我们使用多个核糖核酸测序（RNA-Seq）数据集，试图确定 CF 和巨噬细胞在再生（）和非再生（+）心脏整体修复反应中的相对贡献。我们对心肌和心脏成纤维细胞的批量 RNA-Seq 数据集以及心脏巨噬细胞的单细胞 RNA-Seq 数据集进行了分析。MI 特异性途径差异表明，非再生心脏产生更多的 ECM，基质细胞反应更大，与炎症相关，产生更大的趋化梯度招募巨噬细胞，并以高于新生鼠的水平表达危险相关分子模式的受体。与新生鼠相比，这些变化可能导致应激反应途径的升高，在 NF-κB 和激活蛋白-1（AP-1）信号中汇聚。在 MI 后差异很大的促纤维化基因程序为慢性纤维化奠定了基础，因此，7 天以上的新生鼠心脏通常表现出明显较少的再生。我们的分析表明，出生后心脏中巨噬细胞的个体发生转变可能导致抑制再生的有害应激信号。出生后哺乳动物的心脏在梗塞后能够再生，但调节这种行为的细胞、途径和分子尚不清楚。通过比较再生小鼠心脏和年龄较大、非再生心脏的 RNA-Seq 数据集，我们能够识别出再生的标志性生物学过程。我们发现，非再生心脏中的无菌炎症过程上调，在心肌梗死后 3 天启动促纤维化基因程序，可导致心肌疾病。
