Direct Genetic and/or Pharmacologic Reprogramming for Creation of Cardiomyocytes: Is It Real?

Objective: The most recent experimental concept for myocardial regeneration is the direct reprogramming of fibroblasts (FB) into cardiomyocytes (CM) via delivery of genes encoding for CM-specific transcription factors and/or supporting small molecules or proteins. A multitude of reprogramming protocols has been reported, but there is no consensus regarding the best strategy for further translational development. We therefore conducted an extensive literature search and systematically evaluated efficiency and reproducibility.

Methods and Results: Customized literature searches were conducted in PubMed, Embase, and Web of Science using permutations of 26 keywords, and 9,657 references were collected. After applying defined restriction criteria, 80 relevant articles were identified, with 76 suitable for quantitative analysis. In vitro, seven articles described the direct conversion of FB to CM by “non-specific” stimuli such as 5-azacytidine, HIF-1a, TGF-β1, and electrostimulation. Individual sarcomeric proteins were up-regulated, but efficiency in terms of contracting cells was 0% throughout. Thirty-eight articles reported on the conversion of rodent FB to CM by forced expression of cardiac transcription factors such as Gata4, Mef2c, and Tbx5 or microRNA, 30 by transduction with viral vector system, and 8 by no viral nucleic acid delivery. Individual sarcomaric protein expression ranged between < 1 and 65%, while the yield of contracting cells ranged between 0 and 2% (median 0.3%). Eight articles describe genetic reprogramming (13 protocols tested) of large animal or human cells, with only three protocols yielding any contractile cells. In 10 articles, “primed conversion” including partial/transient induced de-differentiation was used, with a final CM yield between 0.1 and 5% (median 0.3%). Finally, 13 reports described the in vivo direct reprogramming by vector delivery to infarcted rodent myocardium. Here, quantification of phenotype conversion efficiency was rarely possible, but scar size reduction (median −12%) and improved LVEF (median + 11%) were observed throughout.

Conclusion: A wide range of in vitro FB-to-CM reprogramming protocols has been reported, but true phenotype conversion is a rare event and intergroup reproducibility poor. Surprisingly, in vivo reprogramming vector delivery seems to result in substantial improvements of scar size and heart function in rodent models, but it is not clear whether this is the consequence of actual reprogramming.

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