Prokineticin receptor-1-dependent paracrine and autocrine pathways control cardiac tcf21+ fibroblast progenitor cell transformation into adipocytes and vascular cells

Rehana Qureshi,Mounia Boulberdaa,Canan G Nebigil,Marja Steenman,Michel Kindo,Himanshu Arora

doi:10.1038/s41598-017-13198-2

Abstract

Cardiac fat tissue volume and vascular dysfunction are strongly associated, accounting for overall body mass. Despite its pathophysiological significance, the origin and autocrine/paracrine pathways that regulate cardiac fat tissue and vascular network formation are unclear. We hypothesize that adipocytes and vasculogenic cells in adult mice hearts may share a common cardiac cells that could transform into adipocytes or vascular lineages, depending on the paracrine and autocrine stimuli. In this study utilizing transgenic mice overexpressing prokineticin receptor (PKR1) in cardiomyocytes, and tcf21ERT-creTM-derived cardiac fibroblast progenitor (CFP)-specific PKR1 knockout mice (PKR1tcf−/−), as well as FACS-isolated CFPs, we showed that adipogenesis and vasculogenesis share a common CFPs originating from the tcf21+ epithelial lineage. We found that prokineticin-2 is a cardiomyocyte secretome that controls CFP transformation into adipocytes and vasculogenic cells in vivo and in vitro. Upon HFD exposure, PKR1tcf−/− mice displayed excessive fat deposition in the atrioventricular groove, perivascular area, and pericardium, which was accompanied by an impaired vascular network and cardiac dysfunction. This study contributes to the cardio-obesity field by demonstrating that PKR1 via autocrine/paracrine pathways controls CFP–vasculogenic- and CFP-adipocyte-transformation in adult heart. Our study may open up new possibilities for the treatment of metabolic cardiac diseases and atherosclerosis.

Highlights

Cardiac fibroblast and progenitors (CFPs) derived from epicardium and endothelium respond to a wide range of different stimuli, including hypoxia as well as chemical, mechanical, and electrical signals, during cardiac development and disease[1]
Transgenic mouse model in which PKR1 is overexpressed in the cardiomyocytes (TG-PKR1) has shown that PKR1 signaling upregulates the expression of its own ligand, prokineticin-2, as a secretome, inducing the proliferation and differentiation of epicardial progenitor cells (EPDCs), thereby promoting neovascularization[9]
We identified a novel role for PKR1 signaling in regulating cardiac fat tissue and vascular network development, suggesting that defective PKR1 signaling in obesity could be a key contributor to metabolic cardiac diseases and atherosclerosis

Summary

Introduction

Cardiac fibroblast and progenitors (CFPs) derived from epicardium and endothelium respond to a wide range of different stimuli, including hypoxia as well as chemical, mechanical, and electrical signals, during cardiac development and disease[1]. Whether cardiac tcf21+ CFPs undergo adipocyte or vascular-transformations in the adult heart depending on the stimuli and different environmental contexts has not yet been studied. Prokineticin-2/PKR1 signaling inhibits the differentiation of adipocyte progenitor cells into adipocytes. It promotes epithelial-to-mesenchymal transition (EMT) in the epicardial Wt1+lineage during the development of coronary vasculature and growth of the ventricular wall[8]. Prokineticin-2, via PKR1, induces the differentiation of adult epicardial explant cultures into endothelial and vascular cells[9]. Transgenic mouse model in which PKR1 is overexpressed in the cardiomyocytes (TG-PKR1) has shown that PKR1 signaling upregulates the expression of its own ligand, prokineticin-2, as a secretome, inducing the proliferation and differentiation of epicardial progenitor cells (EPDCs), thereby promoting neovascularization[9]. We identified a novel role for PKR1 signaling in regulating cardiac fat tissue and vascular network development, suggesting that defective PKR1 signaling in obesity could be a key contributor to metabolic cardiac diseases and atherosclerosis

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Results

Conclusion