Towards Direct Reprogramming of Cardiac Cells to Induce Regeneration in the Heart

Researchers have for some years proposed reprogramming of scar tissue cells in the injured heart as a way to produce a regrowth of healthy tissue, an outcome that does not normally occur. The heart is one of the least regenerative organs in mammals, and injury produces scarring and loss of function. A great deal of effort has gone towards the establishment of cell therapies to treat heart injuries, with some limited success, but reprogramming of native cells may prove to be a better option in the long term. As noted here, however, there is a great deal of work left to accomplish between the present state of the art and a future in which scar tissue in the heart can be safely reprogrammed into functional muscle.

The heart is composed of different types of cells, and cardiac function is carefully regulated, not only by cardiomyocytes, but also by other cells, such as vascular endothelial cells and fibroblasts. Cardiomyocytes account for approximately 30% of all cells in the heart, and at least 50% of the remaining cells are non-cardiomyocytes. Cardiomyocytes are terminally differentiated cells with no potential for self-renewal; cardiomyocytes that become necrotic due to myocardial infarction, heart failure, or other cardiac diseases are therefore replaced by proliferating fibroblasts. This situation results in scarring of the affected site due to the formation of fibrotic tissue. These fibrotic changes reduce the cardiac systolic function, and arrhythmia caused by scar tissue has a poor prognosis.

One promising approach to cardiac regeneration is to differentiate stem cells, such as induced pluripotent stem cells (iPS cells) into cardiomyocytes outside the body, and then transplant the differentiated cardiomyocytes into the body. However, generating the large numbers of cells required to replace as many as 1 billion cardiomyocytes lost to myocardial infarction or failing heart incurs enormous costs. It also poses other limitations, such as the presence of residual stem cells undergoing oncogenesis, and a low survival rate of transplanted cells

In 2010, we reported a novel strategy for the direct reprogramming of fibroblasts into cardiomyocytes. Based on these results, there are currently three possible pathways for the creation of cardiac muscle from fibroblasts. The three pathways can be summarized as follows: (1) full reprogramming of fibroblasts into iPS cells and subsequent cardiac differentiation, (2) partial reprogramming of fibroblasts into cardiac progenitor cells and subsequent differentiation, and (3) direct reprogramming of fibroblasts into cardiomyocytes. We proposed the concept of "direct cardiac reprogramming" in place of this conventional method of cell transplantation. This is a technique that converts cardiac fibroblasts, which are present in large numbers in the myocardium in cardiac direct reprogramming, into cardiomyocytes.

Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.


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