Mesenchymal–endothelial transition contributes to cardiac neovascularization

Abstract

Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal-transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial cell like phenotype after acute ischemic cardiac injury. Fibroblast derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast derived endothelial cells, reduces post infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal to endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial-transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…This possibility is unexplored in the adult heart but may reconcile the apparent differences between lineagetracing studies on the origin of the cardiac fibroblast. In a final twist, evidence has recently emerged that adult myofibroblasts can undergo mesenchymal-to-endothelial transition (MEndT) and adopt an endothelial phenotype in an acute cardiac ischemia setting (Ubil et al, 2014). The transition appears to be complete, with myofibroblast-derived endothelial cells exhibiting the functional characteristics of native endothelial cells.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…GAGs, glycosaminoglycosans. environmental cues, interstitial cells exhibit phenotypic changes (84)(85)(86), leading to transitions from inflammatory to reparative phenotypes (87). Through their transient induction and incorporation into the matrix, matricellular proteins may play a critical role in regulating cell differentiation, contributing to the cellular plasticity observed in healing tissues through direct actions and via modulation of growth factor-mediated pathways.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…More recent studies in the heart have shown that the Col1a2 promoter drives expression specifically in fibroblasts, so these mice may represent a useful model for selective genetic manipulation of fibroblasts and myofibroblasts in the heart [145][146][147]. A drawback of the Col1a2 approach however is that it is not selective for fibroblasts in the heart over other sources of fibroblasts (e.g.…”