Division of Cardiology, Department of Medicine, David Geffen School of Medicine.
UCLA Cardiovascular Theme, David Geffen School of Medicine.
JCI Insight. 2020 Dec 17;5(24):140628. doi: 10.1172/jci.insight.140628.
Cardiac fibrosis is a pathophysiologic hallmark of the aging heart, but little is known about how fibroblast proliferation and transcriptional programs change throughout the life span of the organism. Using EdU pulse labeling, we demonstrated that more than 50% of cardiac fibroblasts were actively proliferating in the first day of postnatal life. However, by 4 weeks, only 10% of cardiac fibroblasts were proliferating. By early adulthood, the fraction of proliferating cardiac fibroblasts further decreased to approximately 2%, where it remained throughout the rest of the organism's life. We observed that maximal changes in cardiac fibroblast transcriptional programs and, in particular, collagen and ECM gene expression both in the heart and cardiac fibroblast were maximal in the newly born and juvenile animal and decreased with organismal aging. Examination of DNA methylation changes both in the heart and in cardiac fibroblasts did not demonstrate significant changes in differentially methylated regions between young and old mice. Our observations demonstrate that cardiac fibroblasts attain a stable proliferation rate and transcriptional program early in the life span of the organism and suggest that phenotypic changes in the aging heart are not directly attributable to changes in proliferation rate or altered collagen expression in cardiac fibroblasts.
心脏纤维化是衰老心脏的一种病理生理标志，但对于成纤维细胞增殖和转录程序在整个生物体寿命中如何变化知之甚少。通过 EdU 脉冲标记，我们证明在出生后第一天，超过 50%的心脏成纤维细胞正在积极增殖。然而，到 4 周时，只有 10%的心脏成纤维细胞在增殖。到成年早期，增殖的心脏成纤维细胞的比例进一步下降到约 2%，并在生物体的余生中保持不变。我们观察到，心脏成纤维细胞转录程序的最大变化，特别是心脏和心脏成纤维细胞中胶原和 ECM 基因表达的最大变化，在新生和幼年动物中最大，并随生物体衰老而减少。对心脏和心脏成纤维细胞中的 DNA 甲基化变化的检查表明，年轻和老年小鼠之间的差异甲基化区域没有明显变化。我们的观察表明，心脏成纤维细胞在生物体寿命的早期就达到了稳定的增殖率和转录程序，这表明衰老心脏的表型变化并非直接归因于心脏成纤维细胞增殖率的变化或胶原表达的改变。
