Study Demonstrates Potential of Direct Reprogramming as Strategy for Cardiac Regeneration After Myocardial Infarction

Researchers from the University of Tsukuba, Tsukuba, Japan, have shown how cells in the scar tissue of an injured heart can be converted to heart muscle cells.

Researchers have long sought to find a way to reprogram fibroblasts, cells that produce the connective tissue in a scar, to cardiomyocytes, the working heart muscle cells. Previous studies have shown that cardiomyocytes appear to be formed by directly injecting a harmless virus carrying a set of cardiac transcription factors, proteins that drive the expression of genes that heart muscle cells need for their development and function, into the heart of rodents after a heart attack. However, the origin and functional significance of these newly formed heart muscle cells has not yet unequivocally been determined.

“Direct cardiac reprogramming holds great potential for cardiac regeneration and the treatment of myocardial infarction,” says lead author Professor Masaki Ieda. “However, when transcription factors are introduced, apparent cardiomyocytes may be formed either by converting fibroblasts to new cardiomyocytes or by fusing fibroblasts with existing cardiomyocytes. The difference is that only the former process, which we call ‘direct reprogramming’, significantly contributes to regeneration. In this study, our goal was to determine how new cardiomyocytes are formed when cardiac transcription factors are introduced after myocardial infarction.”

To achieve their goal, the researchers first generated mice in which all cells emitted red fluorescence. However, the mice were modified in a way that the fibroblasts emitted green fluorescence after treatment with the drug tamoxifen. As a result, when looking at the heart after treatment with tamoxifen, cells that emitted both red and green fluorescence indicated that cell fusion between fibroblasts and cardiomyocytes had occurred. Conversely, the presence of green fluorescence indicated that direct reprogramming of fibroblasts to cardiomyocytes had occurred.

Equipped with the tools to tackle their research question, researchers used a mouse model of heart attack and treated the mice with tamoxifen. While there was no direct reprogramming in a control group, the researchers found 1-1.5% of directly reprogrammed cells when a virus carrying cardiac transcription factors was injected into the mice. Both groups exhibited minimal cell fusion. These results suggest that the main route of generating new heart muscle cells by this method is via reprogramming fibroblasts directly to cardiomyocytes.

“These are striking results that show that fibroblasts can be directly reprogrammed to cardiomyocytes. Our findings demonstrate the exciting potential of direct reprograming as a strategy for cardiac regeneration after myocardial infarction,” says Professor Ieda. 

Reference

1. Isomi M, Sadahiro T, Yamakawa H, et al. Overexpression of Gata4, Mef2c, and Tbx5 generates induced cardiomyocytes via direct reprogramming and rare fusion in the heart. Circulation. 2021 May 25; 143(21): 2123-2125. doi: 10.1161/CIRCULATIONAHA.120.052799