Direct Cardiac Reprogramming

Abstract

The discovery of induced pluripotent stem cells changed the field of regenerative medicine and inspired the technological development of direct reprogramming or the process by which one cell type is directly converted into another without reverting a stem cell state by overexpressing lineage-specific factors. Indeed, direct reprogramming has proven sufficient in yielding a diverse range of cell types from fibroblasts, including neurons, cardiomyocytes, endothelial cells, hematopoietic stem/progenitor cells, and hepatocytes. These studies revealed that somatic cells are more plastic than anticipated, and that transcription factors, microRNAs, epigenetic factors, secreted molecules, as well as the cellular microenvironment are all important for cell fate specification. With respect to the field of cardiology, the cardiac reprogramming presents as a novel method to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells in situ. The first in vivo cardiac reprogramming reports were promising to repair infarcted hearts; however, the low induction efficiency of fully reprogrammed, functional induced cardiomyocyte-like cells has become a major challenge and hampered our understanding of the reprogramming process. Nevertheless, recent studies have identified several critical factors that may affect the efficiency and quality of cardiac induction and have provided new insights into the mechanisms of cardiac reprogramming. Here, we review the progress in direct reprogramming research and discuss the perspectives and challenges of this nascent technology in basic biology and clinical applications.

Building and re-building the heart by cardiomyocyte proliferation

“…The direct reprogramming of non-muscle cells into cardiomyocytelike cells by infecting or treating the heart with defined factors would achieve this goal. Although there have been provocative recent demonstrations of the potential of this approach, the low efficiency of reprogramming vectors is a target area for improvement (Chen et al, 2012;Ieda et al, 2010;Qian et al, 2012;Song et al, 2012; reviewed by Sadahiro et al, 2015). The stimulation of cardiomyocyte proliferation, as discussed in this Review, thus remains an attractive approach for regenerating the heart.…”

Strip and Dress the Human Heart

“…Therapies aiming at the biological regeneration of the heart by remuscularization address the underlying cause of the disease in a straight forward; however, clinically not yet accomplished way by (Figure) (1) implantation of cardiomyocytes, cardiac progenitor cells, or other cells with cardioprotective paracrine activity, [3][4][5] (2) changing the fate of the myocardial scar's stroma cells toward a cardiomyocyte lineage by in situ reprogramming, 6 or (3) tissue engineered heart repair with the aim to create structurally and functionally defined surrogate heart muscle in vitro for precise applications in vivo. 7 Cell sheet 8 and hydrogel-based 9,10 tissue engineering modalities are undoubtedly most advanced toward clinical application.…”

Recent Advances in Hypertrophic Cardiomyopathy: A System Review

“…In vivo direct cardiac reprogramming of somatic cells into cardiomyocytes is a potential offshoot of current reprogramming techniques but has not yet been tested in humans [71]. For HCM in particular, the possibility of converting cardiac fibroblasts into functional cardiomyocytes could theoretically ameliorate hypertrophy and improve diastolic function.…”