Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Institute of Cellular Medicine, Newcastle University, United Kingdom.
Transplantation. 2019 Apr;103(4):e64-e73. doi: 10.1097/TP.0000000000002589.
Fibrosis is a universal finding in chronic allograft dysfunction, and it is characterized by an accumulation of extracellular matrix. The precise source of the myofibroblasts responsible for matrix deposition is not understood, and pharmacological strategies for prevention or treatment of fibrosis remain limited. One source of myofibroblasts in fibrosis is an endothelial-to-mesenchymal transition (EndMT), a process first described in heart development and involving endothelial cells undergoing a phenotypic change to become more like mesenchymal cells. Recently, lineage tracing of endothelial cells in mouse models allowed studies of EndMT in vivo and reported 27% to 35% of myofibroblasts involved in cardiac fibrosis and 16% of isolated fibroblasts in bleomycin-induced pulmonary fibrosis to be of endothelial origin. Over the past decade, mature microRNAs (miRNAs) have increasingly been described as key regulators of biological processes through repression or degradation of targeted mRNA. The stability and abundance of miRNAs in body fluids make them attractive as potential biomarkers, and progress is being made in developing miRNA targeted therapeutics. In this review, we will discuss the evidence of miRNA regulation of EndMT from in vitro and in vivo studies and the potential relevance of this to heart, lung, and kidney allograft dysfunction.
纤维化是慢性移植物功能障碍的普遍发现，其特征是细胞外基质的积累。负责基质沉积的肌成纤维细胞的确切来源尚不清楚，预防或治疗纤维化的药物策略仍然有限。纤维化中肌成纤维细胞的一个来源是内皮细胞向间充质转化（EndMT），这是首先在心脏发育中描述的过程，涉及内皮细胞发生表型变化，变得更像间充质细胞。最近，在小鼠模型中对内皮细胞进行谱系追踪，允许在体内研究 EndMT，并报告心脏纤维化中涉及的肌成纤维细胞有 27%至 35%和博来霉素诱导的肺纤维化中分离的成纤维细胞有 16%来源于内皮细胞。在过去十年中，成熟 microRNAs（miRNAs）越来越多地被描述为通过靶向 mRNA 的抑制或降解来调节生物过程的关键调节剂。miRNAs 在体液中的稳定性和丰度使其成为有吸引力的潜在生物标志物，并且在开发 miRNA 靶向治疗方面正在取得进展。在这篇综述中，我们将讨论体外和体内研究中 miRNA 调节 EndMT 的证据，以及这对心脏、肺和肾脏移植物功能障碍的潜在相关性。
