Augmenting canonical Wnt signalling in therapeutically inert cells converts them into therapeutically potent exosome factories

Abstract

Cardiosphere-derived cells (CDCs) are therapeutic candidates with disease-modifying bioactivity, but their variable potency has complicated their clinical translation. Transcriptomic analyses of CDCs from human donors have revealed that the therapeutic potency of these cells correlates with Wnt/β-catenin signalling and with β-catenin protein levels. Here, we show that skin fibroblasts engineered to overexpress β-catenin and the transcription factor Gata4 become immortal and therapeutically potent. Transplantation of the engineered fibroblasts into a mouse model of acute myocardial infarction led to improved cardiac function and mouse survival. And in the mdx mouse model of Duchenne muscular dystrophy, exosomes secreted by the engineered fibroblasts improved exercise capacity and reduced skeletal-muscle fibrosis. We also demonstrate that exosomes from high-potency CDCs exhibit enhanced levels of miR-92a (a known potentiator of the Wnt/β-catenin pathway), and that they activate cardioprotective bone-morphogenetic-protein signalling in cardiomyocytes. Our findings show that the modulation of canonical Wnt signalling can turn therapeutically inert mammalian cells into immortal exosome factories for cell-free therapies.

EDITORIAL SUMMARY

Overexpression of β-catenin and the transcription factor Gata4 in skin fibroblasts converts them into therapeutically active cells that secrete reparative exosomes as shown in mice models of myocardial infarction and Duchenne muscular dystrophy.