Cardiovascular regenerative therapeutics via synthetic paracrine factor modified mRNA

Abstract

The heart has a limited capacity for regeneration following injury. Recent strategies to promote heart regeneration have largely focused on autologous and allogeneic cell-based therapy, where the transplanted cells have been suggested to secrete unknown paracrine factors that are envisioned to promote endogenous repair and/or mobilization of endogenous heart progenitors. Here, we discuss the importance of paracrine mechanisms in facilitating replication of endogenous epicardial progenitor cells in the adult heart and signaling their subsequent reactivation and de novo differentiation into functional cell types such as endothelial cells and cardiomyocytes. Moreover, we discuss the use of a novel modified RNA technology in delivering such therapeutic paracrine factors into myocardium following injury. These studies suggest that modified mRNA may be a valuable experimental tool for the precise in vivo identification of paracrine factors and their downstream signaling that may promote heart repair, cardiac muscle replication, and/or heart progenitor mobilization. In addition, these studies lay the foundation for a new clinically tractable technology for a cell-free approach to promote heart regeneration.

Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair

“…MI causes death of cardiac myocytes and triggers local inflammatory responses and the compensatory scar formation, leading to pathological remodeling and ultimately heart failure (HF) [2]. Recent experimental therapies for cardiac repair primarily focus on revascularization and regeneration of impaired myocardium [3–5]. However, to break the vicious cycle of MI-to-HF, it is critical to not only promote revascularization of the ischemic tissue but also modulate the over-activated and prolonged inflammation following myocardial injury [6].…”

Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery

“…Previous reports have demonstrated that gene expression is transient yet highly efficient following modRNA transfection ( 15 , 25 , 26 ), so it has been used as a therapeutic delivery agent in many studies ( 27 – 29 ). We have also successfully applied hVEGF A modRNA in promoting murine cardiac regeneration after myocardial infarction ( 14 , 16 ).…”

“…We have previously demonstrated that the modified mRNA (modRNA) technology has some unique advantages over traditional genetic manipulation methods ( 14 , 15 ). We have demonstrated both in vitro ( 15 ) and in vivo ( 16 ) that VEGF A modRNA directs cell fate decision of cardiovascular progenitors and promotes vascular regeneration in adult mouse heart after myocardial infarction ( 16 ).…”

Harnessing Epicardial Progenitor Cells and Their Derivatives for Rescue and Repair of Cardiac Tissue After Myocardial Infarction

“…Analysis of genes expressed by epicardial cells indicate that the epicardium is a notable source of trophic, cytoprotective and angiogenic factors [38,76–79]. In a mouse model of MI, Zhou et al (2011) demonstrated that treatment with murine EPDC-conditioned medium reduced infarct size and improved cardiac function post-MI [38].…”