Abstract
Today, the only available curative therapy for end stage congestive heart failure (CHF) is heart transplantation. This therapeutic option is strongly limited by declining numbers of available donor hearts and by restricted long-term performance of the transplanted graft. The disastrous prognosis for CHF with its restricted therapeutic options has led scientists to develop different concepts of alternative regenerative treatment strategies including stem cell transplantation or stimulating cell proliferation of different cardiac cell types in situ. However, first clinical trials with overall inconsistent results were not encouraging, particularly in terms of functional outcome. Among other approaches, very promising ongoing pre-clinical research focuses on direct lineage conversion of scar fibroblasts into functional myocardium, termed “direct reprogramming” or “transdifferentiation.” This review seeks to summarize strategies for direct cardiac reprogramming including the application of different sets of transcription factors, microRNAs, and small molecules for an efficient generation of cardiomyogenic cells for regenerative purposes.
Highlights
Since cardiomyocytes have a very limited capacity to divide in the adult heart, wound healing after cardiac injury results in fibrotic scar formation at the affected site rather than cardiac muscle regeneration [1,2,3]
Apart from cardiomyocytes, the adult heart consists of many noncardiogenic cell types, the majority of which are fibroblasts [2]
In the first published reports (e.g., [15,22,50]) the evaluation of reprogramming efficiency mostly relied on non-functional measurements, such as the detection of fluorescent proteins driven by the activation of cardiomyocyte-specific promoters or the expression of cardiac-specific genes including those encoding for cardiac cytoskeletal proteins, cardiac transcription factors, or cardiomyocyte ion channel proteins [25,26]
Summary
Since cardiomyocytes have a very limited capacity to divide in the adult heart, wound healing after cardiac injury results in fibrotic scar formation at the affected site rather than cardiac muscle regeneration [1,2,3]. As early as 1987, Davis and colleagues [8] already induced myogenic features in fibroblasts by ectopic expression of the muscle-specific transcription factor MyoD This direct conversion process is characterized by a progressive activation of the target cell program while concomitantly suppressing the starting cell profile [9]. Cardiomyocytes are a very complex cell type with elaborate sarcomeric structures In their mature form they usually do not divide and in situ they are integrated in an advanced electrophysiological network. These are only some of the issues that have to be addressed when trying to generate functional iCMs. This article seeks to comprehensively review different strategies for direct cardiac reprogramming by elucidating the possibilities for cardiac regeneration and discussing the remaining challenges before a clinical application may become reality. Direct Lineage Reprogramming/Conversion of Fibroblasts into Cardiomyocytes in Vitro
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