PHF7: A Key Factor in Reprogramming Fibroblasts Into Cardiomyocytes Following Myocardial Infarction

By Glynnis Garry, M.D.

Cardiology Fellow

Heart failure is the leading cause of death and health care expenditure worldwide. After myocardial infarction, there is massive cardiomyocyte death and proliferation of the fibroblast population in the heart, which leads to scar and ischemic cardiomyopathy. The proximal cause of this pathophysiological cascade is that the adult human heart has no resident stem cell or regenerative capacity. Currently, the only definitive therapy for end-stage heart failure is either a left ventricular assist device or heart transplantation, with both bearing significant risks and the latter a scarce and limited resource. Thus, we have pursued identification of novel strategies to remuscularize the failing myocardium.

At UTSW, one of the approaches taken in the laboratory of Eric Olson, Ph.D., is that of direct cardiac reprogramming. With this approach, we deliver reprogramming factors targeting the resident activated fibroblasts following myocardial infarction to induce cell fate transition from a scar-forming fibroblast into a functional cardiac-like myocyte. While this process is possible, efficiency has been limited in adult and human cells. Previously, in my postdoctoral work under the mentorship of Dr. Olson, we discovered the protein PHF7 to be a potent activator of this process when added to previously studied reprogramming cocktails. PHF7 markedly induced reprogramming in adult human cells in vitro, and through mechanistic studies we identified that PHF7 achieves this by closing chromatin at fibroblast enhancers and opening chromatin at cardiac enhancers.

At #AHA23, I presented our work undertaking preclinical studies assessing the ability of PHF7 to induce reprogramming in vivo following myocardial infarction and recover cardiac function in the mouse heart. We delivered a series of PHF7 cocktails by a single intramyocardial injection following LAD ligation. The PHF7 cocktails not only induced reprogramming but also improved ejection fraction by 15-30% and survival as compared to controls at four months following myocardial infarction. We further identified that PHF7 was sufficient to induce reprogramming and improve cardiac function when delivered as a single factor following infarction. Of note, this is the first report of a single factor inducing cardiac reprogramming in vivo following myocardial infarction. While there is still a long way to go, it is our hope that this protein and other similar epigenetic factors will accelerate the process of reprogramming to the bedside as a viable therapeutic option.

X (formerly known as Twitter) posts by @glynnis_garry