Insulin-Like Growth Factor 1 Receptor-Dependent Pathway Drives Epicardial Adipose Tissue Formation After Myocardial Injury

Abstract

Background Epicardial adipose tissue (EAT) volume and coronary artery disease are strongly associated, even after accounting for overall body mass. Despite its pathophysiological significance, the origin and paracrine signaling pathways that regulate EAT’s formation and expansion are unclear. Methods We used a novel modified mRNA (modRNA)-based screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the adult heart. Results Using two independent lineage tracing strategies in murine models, we show that cells originating from the Wt1+ mesothelial lineage, which includes epicardial cells, differentiate into EAT following myocardial infarction (MI). This differentiation process required Wt1 expression in this lineage and was stimulated by insulin-like growth factor 1 receptor (IGF1R) activation. IGF1R inhibition within this lineage significantly reduced its adipogenic differentiation, in the context of exogenous, IGF1 modRNA stimulation. Moreover, IGF1R inhibition significantly reduced Wt1-lineage cell differentiation into adipocytes after MI. Conclusions Our results establish IGF1R signaling as a key pathway that governs EAT formation in the context of myocardial injury by redirecting the fate of Wt1+ lineage cells. Our study also demonstrates the power of modRNA-based paracrine factor library screening to dissect signaling pathways that govern progenitor cell activity in homeostasis and disease.

Interplay of cell–cell contacts and RhoA/ MRTF ‐A signaling regulates cardiomyocyte identity

“…Recent evidence suggests that IGF1R signaling also governs epicardial adipose tissue formation in the context of myocardial injury in mice by redirecting the fate of Wt1 + lineage cells (Zangi et al , ). Wt1 expression seems to be required for such process (Zangi et al , ).…”

Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria

“…+ mesothelial cells originating in the lateral plate mesoderm can give rise to several visceral fat depots as well as to the epicardium and sup-epicardial adipocytes (12,40). These early mesodermal WT1…”

“…In addition to natriuretic peptides, other factors produced in different pathological contexts could drive the transition of epicardium progenitors to fat. For instance, IGF1R could induce the aEPDCs-derived adipocytes following myocardial infarction (12). Moreover, rapid atrial beating in pigs and permanent AF in humans are associated with the expression of several genes able to regulate AT accumulation in human and pig atrial myocardium, a phenomenon attributed to an insufficient supply of oxygen and nutriments (11).…”

“…In adult mice overexpressing the adipogenic transcriptional factor peroxisome proliferator-activated receptor-γ (PPARγ) and after massive acute myocardial injury, some adipocytes derived from the epicardium were detected in the ventricle (10,11). Protein factors such as Insulin-like growth factor 1 receptor (IGF1R) govern the formation of ventricular EAT after acute myocardial infarction (12).…”

Synthetic MicroRNAs Stimulate Cardiac Repair

“…The short but sufficient pharmacokinetics (12 days) for induction of cardiac regeneration indicates similar to modified mRNA (modRNA) (8,9), short-term gene manipulation immediately post MI may lead to substantial effects on cardiac (7) and cardiovascular (8) regeneration or formation of epicardial fat (9). The fact that hsa-miR-590-3p or hsa-miR-199a-3p induce CMs proliferation and cardiac regeneration post MI indicate that the miRNAs other strands (hsa-miR-590-5p or hsa-miR-199a-5p), that were delivered in the AAV9 vectors, had small or no influence on the beneficial effects observed by the two key candidate miRNA mimics.…”