Prokineticin receptor-1 signaling promotes Epicardial to Mesenchymal Transition during heart development

Abstract

The epicardium plays an essential role in coronary artery formation and myocardial development. However, signals controlling the developing epicardium and epicardial-mesenchymal transition (EMT) in the normal and diseased adult heart are studied less rigorously. Here we investigated the role of angiogenic hormone, prokineticin-2 and its receptor PKR1 in the epicardium of developing and adult heart. Genetic ablation of PKR1 in epicardium leads to partial embryonic and postnatal lethality with abnormal heart development. Cardiac developmental defects are manifested in the adult stage as ischemic cardiomyopathy with systolic dysfunction. We discovered that PKR1 regulates epicardial-mesenchymal transition (EMT) for epicardial-derived progenitor cell (EPDC), formation. This event affects at least three consequential steps during heart development: (i) EPDC and cardiomyocyte proliferation involved in thickening of an outer compact ventricular chamber wall, (ii) rhythmicity, (iii) formation of coronary circulation. In isolated embryonic EPDCs, overexpression or activation of PKR1 alters cell morphology and EMT markers via activating Akt signaling. Lack of PKR1 signal in epicardium leads to defective heart development and underlies the origin of congenital heart disease in adult mice. Our mice provide genetic models for congenital dysfunction of the heart and should facilitate studies of both pathogenesis and therapy of cardiac disorders in humans.

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

“…Mice lacking PKR1 in their epicardial cells displayed a partial embryonic lethality, due to impaired EMT in their hearts. PKR1 signaling promotes the proliferation and EMT of Wt1 + lineage and for their subsequent differentiation into endothelial and vascular SMCs during heart development [18]. However, PKR1 is involved in the reverse process, Mesenchymal to epithelial/epicardial transformation (MET), in the glomerular development of developing kidney, leading to differentiation of kidney progenitors into vasculogenic cells type [41].…”

“…We recently showed that an angiogenic [15,16] and anorectic hormone [17] prokineticin-2 (PK2), acting via its receptor, PKR1, triggers the EMT of epicardial lineages during cardiogenesis [18], and promotes the vasculogenic differentiation of EPDCs derived from developing mouse hearts [19,20]. PK2/PKR1 signaling prevents the conversion of mouse adipocyte progenitors into adipocytes, and lack of PKR1 in adipose tissue induces obesity [21].…”

Obesity Peptide: Prokineticin

“…PKR1 signaling in kidney is essential for nephron development during embryogenesis [38]. Recently, it has been shown that mutant mice with targeted PKR1 gene disruptions in nephron progenitors exhibited partial embryonic and postnatal lethality due to hypoplastic kidneys with premature glomeruli and necrotic nephrons.…”

“…In developing heart, PKR1 regulates epicardial-mesenchymal transition (EMT) to form epicardial-derived progenitor cell (EPDC) [38]. Genetic ablation of PKR1 in epicardium leads to ventricular hypoplasia and septal defects during embryogenesis.…”

“…AT proliferative phenotype has switch to AT hypertrophic phenotype when these mice were treated with a high-fat diet, implicating high calorie intake is involved in the conversion of hyperplasia to hypertrophy. In isolated preadipocytes, PKR1 activation suppresses proliferation and adipogenic differentiation [38].…”