Understanding Metabolism and Maturation of iPSC Cardiomyocytes

By Amanda Chase, PhD

1 out of every 4 deaths in the United States is caused by cardiovascular disease (CVD). Understanding CVD and potential treatments is crucial for decreasing the number of deaths. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been shown to be a great tool for modeling CVD and drug screening, and are also being used for transplantation into injured heart muscle as a potential therapy. A limitation to the use of these iPSC-CMs is that they are considered to be immature, similar to early human embryonic cardiomyocytes. To fully realize the potential of iPSC-CMs, they need to be more mature. It has been shown that iPSC-CMs show maturation over a longer period of time in culture, but no work has been done to characterize events that control transitions of cardiac cells during developmental progression. In a paper recently published in Circulation Research (May 2019), Stanford Cardiovascular Institute researchers sought to understand functional and metabolic transitions of cardiac cells during development, which could provide insight into maturing iPSC-CMs.

These efforts were led by Antje Ebert, Ph.D., who is now a group leader at the University of Goettingen, Medical Center in Germany. They used iPSC-CMs that were kept in culture for different lengths of time (early, medium, and late), and then looked at network pathways at each time point and comparing between them. They were able to describe a novel mechanism governing metabolic output during long-term culture. Dr. Ebert explains that “this study shows that iPSC-CMs can serve as a model for studying human cardiomyocyte development progression during maturation. We also show that modulation of cardiomyocyte metabolism during development affects contractility of cardiomyocytes.” That is an important distinction for mature CMs. “Our study provides options for maturing iPSC-CMs, which is extremely useful for disease modeling, drug testing, and future regenerative approaches,” explains senior author Joseph C. Wu, M.D., Ph.D., Director of Stanford Cardiovascular Institute.

Other authors from the Stanford Cardiovascular Institute include Yuanyuan Da, Shirvatsan Sampathkumar, Haodong Chen, Yingxin Li, and Priyanka Garg. Other authors, also Stanford affiliated, include Amit Joshi, Sandra Andorf, Karl Toischer, Gerd Hasenfuss, and Daria Mochly-Rosen. Additional support was provided by Neuroscience Microscopy Service (NIH P30 NS069375), the FACS Core at the Institute for Stem Cell Biology and Regenerative Medicine, and the Stanford Shared FACS facility. Funding was provided by NIH RO1 HL133272, R01 HL130020, R01 HL146690, RO1 HL52141; American Heart Association grant 17MERIT33610009; Burroughs Wellcome Foundation 1015009; Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) Sonderforschungsbereich 1002, Project A12, Project D01, and Project D04.

Dr. Antje Ebert