Direct Cardiac Cellular Reprogramming for Cardiac Regeneration

Cardiac stem cell trials and the new world of cellular reprogramming: Time to move on

“…In this context, many of the challenges of stem cell therapy would appear to be resolved by the attributes of cellular reprogramming, wherein the abundant resource of fibroblasts generated at sites of post-infarct ventricular remodeling could be targeted for in situ conversion (“transdifferentiation”) directly into induced cardiomyocytes (iCMs). Specifically, a direct cellular reprogramming strategy, if sufficiently efficient, would theoretically enable the abundant regeneration of myocardial tissue from scar, and because it is an “in-situ” strategy (i.e., it targets endogenous cells, rather than requiring the injection of exogenous cells into the myocardium) it would largely abrogate the current challenges of exogenous stem cell expansion, injection, electrophysiological integration and survival in the host myocardial syncytium [1, 6, 16]. Of course, while appealing theoretically, it must first be cautioned that cellular reprograming, although novel, may in the end fail to provide any added benefit over the injection of exogenous stem cells.…”

“…With the caveat of wishing to avoid irrational enthusiasm, it can be reported that direct cellular reprograming studies have already demonstrated dramatic improvements in small animal myocardial infarction models, with 30% – 40% increases in post-infarct ejection fraction and up to 50% improvements in fibrosis observed in a growing number of studies [1, 16]. Underlying this favorable case for myocardial regeneration may be the apparent “default” tendency of cells to differentiate towards a cardiomyocyte phenotype, recapitulating the primacy of cardiac development in embryogenesis, which can be facilitated by the “therapeutic” delivery of various combinations of transcription factor master gene switches that are associated with early embryonic cardiac development.…”

“…To this end, while the first successful direct cardiac reprogramming, as reported by Srivastava et al, achieved reprogramming efficiencies of about 7% using administration of the cardio-differentiating transcription factors Gata4, Mef2c and Tbx5, it is encouraging that investigators almost immediately after Srivastava’s report began to better decipher the genetic pathways leading to cardiac cellular differentiation and (successfully) test alternative reprogramming cocktails to enhance reprogramming efficiency [1, 16]. In addition to the incorporation of alternative reprogramming factors in reprogramming cocktails, elucidation of better stoichiometry of transcription factor ratios, use of alternative gene transfer vectors and polycistronic vectors to improve cell targeting, and introduction of small molecule alternates to transcription factor genes quickly followed over the past five years since Srivastava’s landmark foray in this field [16, 17].…”

“…In addition to the incorporation of alternative reprogramming factors in reprogramming cocktails, elucidation of better stoichiometry of transcription factor ratios, use of alternative gene transfer vectors and polycistronic vectors to improve cell targeting, and introduction of small molecule alternates to transcription factor genes quickly followed over the past five years since Srivastava’s landmark foray in this field [16, 17]. …”

“…Small molecule inhibitors of key pro-fibrotic pathways, targeting such pro-fibrotic mediators as transforming growth factor-β (TGF-β) or Rho-associated kinase, have also been thus used to enhance reprogramming efficiency and quality, as evidenced by the percentage of contractile cells and maturation of sarcomeric structures found in cultures of transdifferentiated cells [16]. This and related strategies now often incorporate multi-targeted microRNAs (miRs) to improve the efficiency of reprogramming cocktail components [16]. …”