Risks of Cryopreserving Cells for Drug Testing
By Adrienne Mueller, PhD
January 12, 2021
With cardiovascular disease being the leading cause of death across the globe, pharmaceutical treatments for heart-related disorders are a major avenue of research. One of the main challenges in drug testing is the risk drug tests pose to patients. A new drug may hold the promise of a cure, but it may also have unwanted side-effects. Fortunately, recent decades have seen the development of a fantastic new method for testing pharmaceutical treatments for heart disease without risking patients: stem cells, and specifically, human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs). With this technique, cells are collected from a patient with a cardiovascular condition by routine blood draw or tissue biopsy, and these cells are then treated in a manner that causes them to develop into heart cells, or cardiomyocytes. The hiPSC-CM technique yields patient-specific heart tissue in a dish which can be used for drug tests without risking the patient.
Patient-derived heart cells (hiPSC-CMs) have provided unprecedented opportunity for the high throughput testing of drugs. However, the majority of these drug studies use cells that have undergone cryopreservation for storage. Because the decision to proceed with further development of a drug depends on how cells respond to a treatment, it is critical to know how the process of cryopreservation and recovery affects the function and drug response profile of patient-derived heart cells. A recent study by co-first authors Joe Zhang, PhD, Nadjet Belbachir, PhD and Tiejun Zhang, PhD and senior-author Joseph C. Wu, MD, PhD was recently published in Stem Cell Reports and addresses this important question. Zhang, Belbachir and Zhang et al systemically characterized the molecular and functional properties of fresh hiPSC-CMs and hiPSC-CMs that were recovered after cryopreservation. They showed that fresh and recovered hiPSC-CMs often express different genes, and exhibit different electro-mechanical functions. Even more importantly, recovered hiPSC-CMs show altered drug responses compared to fresh cells and also tend to exhibit enhanced drug-induced arrhythmias. These findings indicate limitations to using cryopreserved stem cells and strongly suggest the need to account for cryopreservation-induced changes in cell profiles when performing drug tests. The use of fresh patient-derived heart cells or the careful use of cryopreserved patient-derived heart cells in future drug studies will improve the predictive accuracy of drug responses and drug toxicity in patients. First author Dr. Joe Zhang summarizes, “The effect of cryopreservation and recovery on hiPSC-CMs has been neglected in the past. Our study draws attention to the fact that altered drug responses of recovered hiPSC-CMs need to be considered in drug testing.”
Other Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Yu Liu, PhD and Rajani Shrestha, PhD.