Cardiomyocyte engineering: The meeting point of transcription factors, signaling networks, metabolism and function

Direct cardiac reprogramming or transdifferentiation is a relatively new and promising area in regenerative therapy, cardiovascular disease modeling, and drug discovery. Effective reprogramming of fibroblasts is limited by their plasticity, that is, their ability to reprogram, and depends on solving several levels of tasks: inducing cardiomyocyte-like cells and obtaining functionally and metabolically mature cardiomyocytes. Currently, in addition to the use of more classical approaches such as overexpression of exogenous transcription factors, activation of endogenous cardiac transcription factors via controlled nucleases, such as CRISPR, represents another interesting way to obtain cardiomyocytes. Therefore, special attention is given to the potential of synthetic biology, in particular the CRISPR system, for the targeted conversion of only certain subpopulations of fibroblasts into cardiomyocytes. However, obtaining functionally and metabolically mature cardiomyocytes remains a challenge despite the range of recently developed approaches. In this review, we summarized current knowledge on the function and diversity of human cardiac fibroblasts and alternative cell sources for in vitro human cardiomyocyte models. We examined in detail the transcription factors that initiate cardiomyogenic reprogramming and their interactions. Additionally, we critically analyzed the strategies used for the metabolic and physiological maturation of induced cardiomyocytes.