The All-Chemical Approach

It has taken a while, but the concept that the terminally differentiated state is immutably stable no longer dominates modern biology. In 1938, Hans Spemann contemplated a fantastical experiment in which transfer of an egg nucleus could redirect a recipient somatic cell to become pluripotent, and Gurdon made this a reality in 1958 by converting gut epithelial cells into whole frogs. Inspired by Gurdon et al, Takahashi and Yamanaka developed the induced pluripotent stem cell (iPSC) technology where 4 transcription factors sufficed in generating PSCs. The last decade has witnessed an explosion in cell fate manipulations. Many somatic cell types were interconverted by the means of transcription factors and epigenetic and cellular pathway modulators. As one of the most difficult cells to regenerate, cardiomyocyte was successfully generated from fibroblasts by introducing cocktails of transcriptions factors. In a recent article in Science, Cao et al reported the successful reprograming of functional cardiomyocytes by small molecules and growth factors. Cao et al devised a 3-step protocol. Human foreskin fibroblasts or human fetal lung fibroblasts were first treated with 9 compounds (9C: CHIR99021, A83-01, BIX01294, AS8351, SC1, Y27632, OAC2, SU16F, and JNJ10198409) that were the outcome of multiple rounds of focused screening. Next, the cells were incubated with a cardiac induction medium containing previously known cardiogenic factors activin A, BMP4, VEGF, and CHIR99021. Finally, human cardiomyocyte-conditioned medium was used to aid maturation. At day 30, 6.6±0.4% cells in the culture were cardiac troponin T positive, a remarkable improvement in efficiency over transcription factor–mediated reprogramming (Figure). The chemically converted cells in many ways resembled CMs derived from human PSCs. They displayed sarcomeric structures, epigenetic signatures, transcriptomes, and electrophysiological properties comparable to early-stage cardiomyocytes. This all-chemical approach represents a major advance for cardiac regeneration. From a cell therapy perspective, it is appealing because it circumvents inadvertent genomic modifications that can occur with genetic methods, and the chemical compounds themselves are nonimmunogenic. Other potential advantages include less variability, tighter dose control, and greater cost-effectiveness if translated clinically. From a chemical biology perspective, a deeper understanding of the protein targets of the compounds and the signals they evoke constitute a new angle on understanding cardiac differentiation and reprogramming mechanisms.