The pericardium is a multilayered structure encompassing and protecting the heart and proximal part of the great vessels. However, it is more than just a protective sac, as it has been reported to regulate the size of the heart, support cardiac homeostasis and harbour cardioprotective macrophages. Although rare, congenital pericardial defects are associated with other congenital heart defects in one third of cases, underlining the close association between pericardial and cardiac development. Despite this, pericardial development remains relatively understudied. Conflicting theories still exist on the developmental origin of the pericardium, suggested by some to derive from heart field progenitors, and proposed by others to share a less specific lineage with other mesothelia across organs.
Hannah Moran and colleagues from the Mosimann lab (Aurora, CO, USA) make strides towards consolidating these contradictory models in an article recently published in Nature Communications. Here, the authors attack the question of pericardial origin from multiple angles, using live imaging timelapses of transgenic zebrafish models expressing overlapping sets of fluorescent reporter constructs. They complement these data with single-cell transcriptional characterisation of lateral plate mesoderm and its derivatives, as well as with zebrafish and rat experimental models of perturbed cardiac development.
By backtracking cells migrating laterally to form the pericardium in live imaging timelapses, Moran et al. revealed that pericardial cells arise from the anterior- and lateral-most portion of the hand2-positive lateral plate mesoderm. This region is distinct from the region cardiac progenitors arise from, although pericardial progenitors initially also express the heart field marker nkx2.5, and the cardiopharyngeal field marker tbx1. However, as development progresses, pericardial precursor cells transcriptionally align more closely with other mesothelial progenitors. Distinguishing pericardial precursor cells from cardiac and other mesothelial populations, pericardial progenitors show relative enrichment of jam2b, sfrp5, tmem88b, nr2f1a, meis2b and twist1a transcripts.
To further explore how the pericardium depends on cardiac tissues during its development, the authors next studied mef2ca/mef2cb-depleted (a model for disrupted heart tube formation) or sox32-mutant (a model resulting in bifid hearts due to absent midline convergence) zebrafish embryos. Interestingly, these embryos developed intact pericardial sacs (two in the cardia bifida model) despite disturbed processes of cardiac morphogenesis. These data further support that the pericardium emerges separately from the rest of the heart during development.
Finally, the authors show that canonical Wnt signalling is transcriptionally enriched in pericardial cells compared to myocardial cells. Chemical Wnt inhibition caused zebrafish embryos to develop pericardia with fewer, but larger, cells. Additionally, neonatal rats injected with isoproterenol and endogenous Wnt inhibitor sFRP1, recapitulating conditions of dilated cardiomyopathy patients, showed stiffer pericardia, despite a minimally impacted cardiac function.
Altogether, this multimodal research firmly positions pericardium formation as an independent process in cardiac morphogenesis, with a distinct spatial and molecular signature. Moreover, this work starts to unravel the developmental relation between the pericardium and the heart. Besides adding another layer to our comprehension of cardiac morphogenesis, defining the developmental relation between the heart and the pericardium promises to deepen our understanding of the association of congenital heart disease with pericardial disease.
