Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies

Abstract

To date, no viable therapeutic options exist for the effective and sustained reversal of cardiac failure, other than heart transplantation and mechanical circulatory assist devices. Therefore, divergent strategies aiming at the de novo formation of contractile tissue, as a prerequisite for the restoration of cardiac pump function, are currently being pursued. Clinical trials involving the transplantation of somatic progenitor cells failed. The search for alternative cell-based strategies to combat the consequences of ischemic injury has sparked widespread interest in the genetic and pharmacologic reprogramming of fibroblasts into cardiomyocytes, harnessing the abundant in vivo pool of cardiac fibroblasts. Here, we provide a comprehensive overview of in vitro and in vivo cardiac reprogramming studies identified in an extensive literature search. We systematically review and evaluate feasibility, efficiency, and reproducibility of the different technologies currently being explored. Finally, we discuss potential safety issues deduced from preclinical studies and identify obstacles that must be overcome before clinical translation.-Klose, K., Gossen, M., Stamm, C. Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies.

Cardiac Myofibroblast and Fibrosis

“…Treatment of cardiac fibrosis is eagerly waited, signaling analysis of various fibroblast states will provide a therapeutic target that is suitable for drug development. Although direct reprogramming of cardiac fibroblasts to cardiomyocytes with chemical compounds is not mentioned in this review, technologies of direct reprogramming are currently in progress [86] and may be another option for the treatment of cardiac fibrosis in future.…”

Myogenin controls via AKAP6 non-centrosomal microtubule organizing center formation at the nuclear envelope

“…Therefore, it would be important in future studies to identify transcription factors that bind to AKAP6β and nesprin-1α promoters and regulate the switch from centrosomal to ncMTOC in these cell types. For this purpose, promising cardiomyocyte and osteoclast "transdifferentiation" tools using multiple transcription factors are available (Chang, Cho, Kim, & Kim, 2019;Ieda et al, 2010;Klose, Gossen, & Stamm, 2019;Yamamoto et al, 2015). Additionally, it appears important to determine in future experiments the mechanisms underlying the preferential binding of myogenin to the isoform-specific promoters, considering the abundance of myogenin binding sites (E-boxes) throughout the genome.…”

“…Formation of ncMTOCs has been associated with cellular differentiation (Sanchez factors are available (Chang, Cho, Kim, & Kim, 2019;Ieda et al, 2010;Klose, Gossen, & Stamm, 2019;Yamamoto et al, 2015). Additionally, it appears important to determine in future experiments the mechanisms underlying the preferential binding of myogenin to the isoform-specific promoters, considering the abundance of myogenin binding sites (E-boxes) throughout the genome.…”

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

“…Addie et al employed a calcium reporter to screen candidate factors and found that the addition of Nkx2.5 to GMTH cocktail maximized reprogramming efficiency, showing more than 50-fold robust calcium oscillation and spontaneous beating [ 79 ]. The candidate-enhancing TFs, such as Ankrd1 , Gata6 , Mef2A , Myocd , Ppargc1a , Tbx20 , Tead4 , and Wt1 , have also been predicted in silico by using computational methods and constructing gene regulatory networks [ 80 ]. In addition, Wang et al found that isoform2 of Mef2C (Mi2) can induce higher reprogramming efficiency than its isoform4 (Mi4) in fibroblasts, and that polycistronic Mi2-GT retrovirus further promoted successful reprogramming for mature CMs, which was consistent with results reported by Hirai et al and Abad et al [ 81 , 82 , 83 ].…”

“…The combination of miR-1and miR-133 with GMTH cocktail generated significantly more matured iCMs [ 93 , 100 ]. Supplementing the viral GMT, GMTH, or GMTHMyMe cocktail with a TGF-β inhibitor or synthetic mimics of miR-1, miR-133, or miR-590 increased the CM reprogramming efficiency and speed of mouse, pig, or human cells, which provided new insight into the molecular mechanism of cardiac reprogramming [ 80 , 101 , 102 ].…”