BS71 Revealing a roadmap for regenerative epicardium by comparing single-cell RNA sequencing of adult and fetal hearts

IntroductionThe epicardium has an essential role in cardiac regeneration as seen in several animals and mammalian neonates. However, in adult mammals, including humans, the epicardium is reportedly quiescent. Researchers have been proposing that reactivating the epicardium may be a potential intervention but it is unclear what the endpoint may look like, or whether the adult heart will be able to properly harness the reactivated epicardium to once again drive regenerative processes.MethodsIn a recently published study, we used available and newly generated single-cell and single-nuclei RNA sequencing data from adult and fetal human hearts and compared the epicardial cells from both stages using an in-depth analysis pipeline. We also used immunohistochemistry and spatial transcriptomics to validate the position of identified cell populations.ResultsWe found a fibroblast-like population of epicardial cells only in the fetal hearts that appeared to express genes associated with EMT and angiogenesis alongside typical epicardial markers. Using spatial transcriptomics and immunohistochemistry, we showed that this epicardial population was further within the myocardium. However, the adult epicardium appeared to be confined to a mesothelial cluster of epicardial cells and was enriched for genes associated with immune, defense, and stress response. Interestingly, we predicted that adult hearts may still receive fetal epicardial communication through paracrine interactions and showed that adult endocardial and endothelial cells receive the majority of fetal-specific signals including a collection of WNT signaling molecules. We also found that human embryonic stem-cell derived epicardial cells were suitably similar to the human fetal epicardium and expressed fetal but not adult epicardial gene programs.Abstract BS71 Figure 1ConclusionsWe conclude that by comparing epicardial transcriptomics from both adult and fetal stages, we have revealed a potential endpoint for restoring epicardial activity, and by showing that adult hearts are still capable of reacting to these endpoints, we have reinforced the validity of regenerative strategies that administer or reactivate epicardial cells in situ.Conflict of InterestNone