The Adult Epicardium
Realizing the Potential for Neovascular Therapy
From the first description of its origins by the Polish-German anatomist Robert Remak in 1855, through to latter day studies into its role in establishing the coronary vasculature (reviewed in1), the embryological epicardium (outermost mesothelial epithelial layer that envelops the developing heart) has intrigued embryologists, cell biologists, and cardiologists alike. The adult epicardium, on the other hand, has been consigned to the overall view that the mature mammalian heart is a terminally differentiated postmitotic organ in which the major structural cell types survive a life time without support from either new vascular or myocardial cells. However, recently the quiescent nature of the adult epicardium has been contested. After appropriate stimulation (by the actin monomer binding protein Thymosin β4) adult epicardium-derived cells (EPDCs) were shown to have the capacity to proliferate, migrate, and differentiate ex vivo into vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts, thus recapitulating their embryonic potency.2 This study unearthed the therapeutic potential of the adult epicardium in terms of inducing neovascularization after myocardial injury. That the adult epicardium may be even more plastic and respond to multiple signaling pathways, to restore pluripotency, is now presented in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, by Urayama et al.3
See accompanying article on page 841
Here the authors describe a novel role for prokineticin signaling in the adult heart. The prokineticins are related to venom-like proteins and have been implicated in a wide range of biological activities including sensory function, circadian rhythms, and survival and differentiation of inflammatory cell lineages. Closer to home prokineticin-2, mediated by its G protein–coupled receptor PRK1, is a survival factor for cardiomyocytes and promotes angiogenesis in a coronary ligation model of myocardial infarction. Up until now, quite how prokineticin-2, via PRK1, may initiate coronary vessel formation (angiogenesis) was unknown. Urayama and colleagues investigated gain and loss of function of the PRK1 receptor in the adult mouse heart and revealed that myocardial PRK1 upregulates the prokineticin-2 ligand, which in turn acts as a paracrine signal to induce pluripotency of postnatal EPDCs (Figure). By studying transgenic mice overexpressing PRK1 in cardiomyocytes, the authors demonstrated that EPDC number increased with concomitant increases in capillary density and coronary arteriole formation. This was mediated by an autocrine upregulation of prokineticin-2 which was shown to promote EPDC differentiation in explant cultures. Importantly the authors were able to show that not only was the effect of the ligand abolished in PRK1-null explants but that in hearts lacking PRK1 the ligand was downregulated alongside reduced capillary density.
Thus the findings by Urayama et al place a previously characterized signaling pathway in a novel setting, whereby prokineticins can induce pluripotency of EPDCs and promote new vessel growth in the postnatal heart. What this study clearly reinforces is that the adult epicardium is a relatively tractable lineage, which can be reprogrammed to adopt a more embryonic pluripotent fate toward the formation of new coronaries. As such adult EPDCs represent a bona fide source of cardiovascular progenitors which have the capacity to respond to multiple cues. Clearly of interest, for future studies, will be to determine mechanistically how prokineticin-2/PRK1 signaling activates adult EPDCs and more importantly whether, in a pharmacological model, prokineticin treatment may offer real therapeutic potential in terms of promoting neovascularization in the injured mammalian heart.
The identification of paracrine factors which stimulate resident cardiac stem or progenitor cells to induce cardioprotection, initiate vascular growth, and promote myocardial repair is a rapidly evolving paradigm toward therapeutic intervention after ischemic heart disease and myocardial infarction. The race is on to translate findings at the level of basic stem cell research toward cell-based therapies in disease within cardiovascular medicine. The phenotype of activated postnatal EPDCs and the epicardial explant system described here,3 and elsewhere,2 may prove invaluable to facilitate biological-based drug discovery,4 for targets which invoke new coronaries, as a significant step toward cardiovascular regeneration.
Lie-Venema HH, van den Akker NM, Bax NA, Winter EM, Maas S, Kekarainen T, Hoeben RC, deRuiter MC, Poelmann RE, Gittenberger-de Groot AC. Origin, fate, and function of epicardium-derived cells (EPCDs) in normal and abnormal cardiac development. Scientific WorldJournal. 2007; 7: 1777–1798.
Urayama K, Guilini C, Turkeri G, Takir S, Kurose H, Messaddeq N, Dierich A, Nebigil CG. Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation. Arterioscler Thromb Vasc Biol. 2008; 28: 841–849.