Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords: Cell lineage specification; Cell migration; Epicardial cells; MicroRNAs; Transcription factors.
© 2025. The Author(s).