Ubil Eric, Duan Jinzhu, Pillai Indulekha C L, Rosa-Garrido Manuel, Wu Yong, Bargiacchi Francesca, Lu Yan, Stanbouly Seta, Huang Jie, Rojas Mauricio, Vondriska Thomas M, Stefani Enrico, Deb Arjun
Department of Cell Biology &Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
Nature. 2014 Oct 30;514(7524):585-90. doi: 10.1038/nature13839. Epub 2014 Oct 15.
Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.
内皮细胞通过经历内皮-间充质转化，成为心脏成纤维细胞的一个亚群，但心脏成纤维细胞是否能转变为内皮细胞命运，并在心脏损伤后直接促进新生血管形成尚不清楚。在此，我们利用遗传命运图谱技术证明，急性缺血性心脏损伤后，心脏成纤维细胞迅速转变为内皮细胞样表型。成纤维细胞衍生的内皮细胞表现出天然内皮细胞的解剖学和功能特征。我们发现转录因子p53调节心脏成纤维细胞命运的这种转变。心脏成纤维细胞中p53的缺失严重减少了成纤维细胞衍生的内皮细胞的形成，降低了梗死后血管密度，并使心脏功能恶化。相反，刺激心脏成纤维细胞中的p53信号通路可增强间充质-内皮转化，增加血管生成并改善心脏功能。这些观察结果表明，间充质-内皮转化有助于受损心脏的新生血管形成，是增强心脏修复的潜在治疗靶点。
