Enabling maturation for improved heart cell modeling

By Amanda Chase, PhD
July 22, 2020

Fourteen years ago, groundbreaking work showed that the development clock could be turned back on adult skin and blood cells to make stem cells that could be turned into any other kind of cell. These cells, called induced pluripotent stem cells (iPSCs), opened the door for improved, personalized patient health by creating an ideal model for studying disease, drug development, and the opportunity to one day do tissue and cell transplants with patient-derived cells to eliminate the risk of rejection. Cardiovascular medicine is one of the many fields that continues to benefit from iPSCs; the ability to produce human cardiomyocytes (heart muscle cells) from iPSCs (iPSC-CMs) has allowed an unprecedented ability to model human heart disease.

Cardiovascular disease (CVD) continues to be a major cause of morbidity and mortality in the United States, second only to cancer. However, there are few drugs to treat or prevent CVD and it is hard to predict who will develop CVD to allow early, more effective preventative measures. iPSC-CMs have the potential to change that. However, current ways of making iPSC-CMs result in a more fetal-like cardiomyocyte, making it harder to model diseases that usually occur in older adults. Having the ability to make more mature iPSC-CMs is crucial for accessing the full potential of iPSC-CMs and the chance to create better therapeutics for CVD.

A team of researchers associated with the Stanford Cardiovascular Institute, led by first authors Dries Feyen, Wesley McKeithan, and Arne Bruyneel and senior author Mark Mercola, Sanford and Joan Weill Scholar and Professor of Cardiovascular Medicine, recently described a new way to enable maturation of iPSC-CMs. Their work was published on July 21 in Cell Reports. Cells, including iPSC-CMs, are maintained by carefully providing the ideal environment for growth, which requires the correct media formulation to provide nutrients and other supplements. Dr. Mercola and his team created a new media that is better adapted to the needs of cardiomyocytes to allow maturation of iPSC-CMs.

When designing the new maturation media, the team accounted for what they knew about the process of cardiomyocyte maturation, and aimed to replicate that in cells. Among other advantages, they were able to provide a balanced exposure to glucose and fats, which allowed processes important for development and maturation. They were able to show that the iPSC-CMs in their newly developed maturation media had hallmarks of more mature adult CMs. Furthermore, they used this media to model complex inherited heart conditions for which disease manifestation was not observed under standard culture conditions.

Engineered heart tissues (EHTs) are an important tool for modeling function of the heart muscle and are a valuable tool for use in finding and/or testing new clinical therapies because they can reproduce normal heart development. Until now, the structure and function of EHTs has been more at the level of a newborn heart instead of the adult heart. The maturation media developed by Dr. Mercola and his team led to improved maturation of the EHTs, as well as enhanced long-term stability.

The findings presented in this Cell Reports paper have the ability to significantly improve iPSC-CMs as a model for cardiovascular diseases. The ability to have more mature iPSC-CMs will allow researchers to study CVD, usually associated with adults, in a more relevant model, and has the potential to be widely applied for both basic and translational research goals.

Other authors associated with the Stanford Cardiovascular Institute include Wesley McKeithan, Arne Bruyneel, Francesca Briganti, Chi Lam, Ricardo Serrano, Christine Wahlquist, Alexander Kreymerman, Michelle Vu, Prashila Amatya, Sara Ranjbarvaziri, Renee Maas, Matthew Greenhaw, Daniel Bernstein, and Joseph Wu.