Castillo-Casas Juan Manuel, Dueñas Ángel, Hernández-Torres Francisco, Carmona Rita, Muñoz-Chápuli Ramón, Dopazo Ana, Álvarez Rebeca, de Luis Enrique Vázquez, Aranega Amelia E, Franco Diego, Lozano-Velasco Estefanía
Cardiovascular Development Group, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, 23071, Jaén, Spain.
Fundación Medina, 18016, Granada, Spain.
Cell Mol Life Sci. 2025 Jun 25;82(1):254. doi: 10.1007/s00018-025-05735-4.
The heart is the first functional organ to develop in the vertebrate embryos. In mice, the primitive tubular heart begins beating at embryonic day (E) 8.0-E.8.5 and undergoes rightward looping to form the atrial and ventricular chambers. The proepicardium, a transient cell cluster at the sinus venous-lateral plate mesenchyme junction migrates onto the heart and gives rise to the embryonic epicardium, a squamous epithelium that plays a key role in cardiac development. Despite advances in understanding epicardial lineage contributions, the molecular mechanisms governing these processes remain poorly understood.
To characterize the transcriptional and post-transcriptional regulation of epicardial development, we performed RNA sequencing at two critical timepoints, proepicardium formation and embryonic epicardium establishment. We analysed differentially expressed coding and non-coding RNAs, focusing on microRNAs and their potential regulatory interactions.
We identified a complex network involving differentially expressed mRNAs, microRNAs and lncRNAs between proepicardium and embryonic epicardium. Notably, with miR-495 and let-7c emerged as key regulators of epicardial cell migration, an essential process for proper epicardium formation and epicardial-derived cell migration. Our findings also reveal that these microRNAs not only regulate target gene expression but also modulate other microRNAs, suggesting a novel regulatory mechanism in epicardial development. Additionally, Foxf1 inhibition modulates let-7c, promoting the expression of key cardiogenic lineage markers in epicardial cells.
Our study highlights the role of Foxf1 in regulating miR-495 and let-7c, which in turn modulate epicardial cell migration and myocardial specification. These finding provide new insights into the intricate interplay between transcription factors and microRNAs in governing cardiogenesis.
心脏是脊椎动物胚胎中第一个发育的功能器官。在小鼠中，原始管状心脏在胚胎第8.0天至8.5天开始跳动，并经历向右环化以形成心房和心室腔。心外膜原基是位于静脉窦-侧板间充质交界处的一个短暂细胞簇，它迁移到心脏上并产生胚胎心外膜，这是一种鳞状上皮，在心脏发育中起关键作用。尽管在理解心外膜谱系贡献方面取得了进展，但控制这些过程的分子机制仍知之甚少。
为了表征心外膜发育的转录和转录后调控，我们在两个关键时间点进行了RNA测序，即心外膜原基形成和胚胎心外膜建立。我们分析了差异表达的编码和非编码RNA，重点关注微小RNA及其潜在的调控相互作用。
我们鉴定了一个复杂的网络，涉及心外膜原基和胚胎心外膜之间差异表达的mRNA、微小RNA和长链非编码RNA。值得注意的是，miR-495和let-7c成为心外膜细胞迁移的关键调节因子，这是心外膜正常形成和心外膜衍生细胞迁移的一个重要过程。我们的研究结果还表明，这些微小RNA不仅调节靶基因表达，还调节其他微小RNA，提示心外膜发育中一种新的调控机制。此外，Foxf1抑制调节let-7c，促进心外膜细胞中关键心脏发生谱系标志物的表达。
我们的研究强调了Foxf1在调节miR-495和let-7c中的作用，而这反过来又调节心外膜细胞迁移和心肌特化。这些发现为转录因子和微小RNA在控制心脏发生中的复杂相互作用提供了新的见解。
