The lymphatic vasculature is a blind-ended network crucial for tissue fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. In contrast, we reveal here that cardiac lymphatic vessels have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple cre-lox based lineage tracing revealed a potential contribution from the hemogenic endothelium during development and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction (MI) promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.

Biological clocks have evolved as an adaptation to life on a rhythmic planet, synchronising physiological processes to the environmental light-dark cycle. Here we examine circadian clock function in Mexican blind cavefish Astyanax mexicanus and its surface counterpart. In the lab, adult surface fish show robust circadian rhythms in per1, which are retained in cave populations, but with substantial alterations. These changes may be due to increased levels of light-inducible genes in cavefish, including clock repressor per2. From a molecular standpoint, cavefish appear as if they experience 'constant light' rather than perpetual darkness. Micos River samples show similar per1 oscillations to those in the lab. However, data from Chica Cave shows complete repression of clock function, while expression of several lightresponsive genes is raised, including DNA repair genes. We propose that altered expression of light-inducible genes provides a selective advantage to cavefish at the expense of a damped circadian oscillator.

The epicardium is essential for mammalian heart development. At present, our understanding of the timing and morphogenetic events leading to the formation of the human epicardium has essentially been extrapolated from model organisms. Here, we studied primary tissue samples to characterise human epicardium development. We reveal that the epicardium begins to envelop the myocardial surface at Carnegie stage (CS) 11 and this process is completed by CS15, earlier than previously inferred from avian studies. Contrary to prevailing dogma, the formed human epicardium is not a simple squamous epithelium and we reveal evidence of more complex structure, including novel spatial differences aligned to the developing chambers. Specifically, the ventricular, but not atrial, epicardium exhibited areas of expanded epithelium, preferential cell alignment and spindle-like morphology. Likewise, we reveal distinct properties ex vivo, such that ventricular cells spontaneously differentiate and lose epicardial identity, whereas atrial-derived cells remained 'epithelial-like'. These data provide insight into the developing human epicardium that may contribute to our understanding of congenital heart disease and have implications for the development of strategies for endogenous cell-based cardiac repair.

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