Abstract 18042: Induction of Cardiac Reprogramming Following Injury Through Delivery of a Single Factor, PHF7

Abstract

Direct reprogramming of resident cardiac fibroblasts into cardiomyocytes is an attractive strategy to restore cardiac function following myocardial infarction (MI). However, canonical and extensively studied reprogramming factors (e.g. Gata4, Mef2c, Tbx5) have shown to be ineffective in reprogramming adult human fibroblasts. Furthermore, current human cocktails require an excess of factors, limiting the clinical translation and safety of this technology. Recently, we undertook a large screen of gene regulatory factors and identified the epigenetic factor PHF7 as the most potent activating factor of adult human fibroblast reprogramming, and described its ability to bind and modify chromatin accessibility at cardiac super enhancers. In this manuscript, we describe the ability of PHF7 to activate adult reprogramming in vitro in absence of canonical reprogramming factors, with PHF7, MEF2C, and TBX5 (PMT) or PHF7 and TBX5 (PT) alone. These minimalist PHF7 cocktails induced broad and unique cardiac transcriptomes in comparison to canonical cocktails. Importantly, when overexpressed in isolation in fibroblasts, PHF7 strongly activated expression of several cardiac transcription factors, establishing its role as a cardiac master regulator. When delivered to the mouse heart following MI, minimalist PHF7 cocktails were found to significantly recover cardiac function and decrease fibrotic scar formation. Interestingly, delivery of PHF7 alone following MI was sufficient to improve cardiac function and induce remodeling through activation of bona fide reprogramming events in vivo as determined by genetic tracing of the Postn MCM lineage. Here, we report for the first time the ability of a single reprogramming factor, PHF7, to induce fibroblast to cardiomyocyte reprogramming and recover cardiac function following injury in vivo.