Researchers have demonstrated the direct conversion of cardiac scar tissues to new heart muscle cells upon injection of virus-delivered transcription factors after a heart attack.
Broken hearts do not heal like broken bones, and in more ways than one. During a heart attack, approximately one billion cells in the heart are lost, none of which are recovered. Unlike tissues of other organs, the heart cannot regenerate after an injury. The only way to heal cardiac wounds is for fibrotic scar tissues to form in the place of damaged myocardium, which can lead to cardiovascular complications such as heart failure, arrhythmia, and even death.
Previous studies with animal models have demonstrated that it is possible to form new heart muscle cells by injecting a harmless virus, known as the Sendai virus, which carries cardiac transcription factors to drive the expression of genes needed for cardiomyocytes to grow and function. However, the exact mechanism behind the formation of these new cells and whether they have any functional significance remained elusive.
In an exciting new study conducted by scientists from the University of Tsukuba, it has been confirmed that cardiac cells can be regenerated through a process known as direct cardiac reprogramming, which involves directly reprogramming cardiac scar tissues (fibroblasts) to become new heart muscle cells (cardiomyocytes), upon the introduction of cardiac transcription factors following myocardial infarction.
The lead author of the study, Professor Masaki Ieda, explained that the introduction of cardiac transcription factors, primarily Gata4, Mef2c, and Tbx5, collectively labelled as GMT, after a heart attack can stimulate the formation of cardiomyocytes in two possible ways: by directly converting fibroblasts into new cardiomyocytes, or by fusing fibroblasts with existing cardiomyocytes. However, only direct reprogramming significantly contributes to cardiac regeneration.
To determine which of these processes is induced by cardiac transcription factors, the team generated mice models of heart attack with cells that emit red fluorescence, and specially engineered them to express green fluorescence after they are subjected to treatment with a drug known as tamoxifen. In these mice, cell fusion between fibroblasts and cardiomyocytes is indicated by the presence of both red and green fluorescence, while the direct reprogramming of fibroblasts to cardiomyocytes is marked by the presence of only green fluorescence.
Their findings revealed the presence of 1 to 1.5 per cent of directly reprogrammed cells when a virus carrying cardiac transcription factors was injected into the mice, and no direct reprogramming in the control group, where mice were not injected with transcription factors. Both control and experimental groups also demonstrated minimal cell fusion, thus suggesting that the primary route of cardiac regeneration is through the reprogramming of fibroblasts to cardiomyocytes.
“These are striking results that show that fibroblasts can be directly reprogrammed to cardiomyocytes. Our findings demonstrate the exciting potential of direct reprogramming as a strategy for cardiac regeneration after myocardial infarction,” commented Professor Ieda. [APBN]
Source: Ieda et al. (2021). Overexpression of Gata4, Mef2c, and Tbx5 Generates Induced Cardiomyocytes Via Direct Reprogramming and Rare Fusion in the Heart. Circulation, 143(21), 2123-2125.