December 6, 2019
Nearly 18 million people die each year from heart disease, making it the leading cause of death in the world. In the United States alone, the economic impact of heart disease exceeds $200 billion, a figure that is expected to rise dramatically.
Patients with heart disease experience progressive, significant declines in quality of life marked by reduced activity and higher hospitalization rates. While lifestyle changes and medical treatments are available to slow the progression to end-stage heart failure, none have the ability to restore normal heart functioning.
At the Institute for Stem Cell and Regenerative Medicine (ISCRM), researchers in multiple labs are using stem cell technology to pioneer novel approaches to treating heart disease that cure rather than manage this chronic disease. In 2018, a study led by ISCRM Director Dr. Charles Murry demonstrated that stem cell-derived cardiomyocytes could be used to regenerate heart tissue in large primates, a major step toward human clinical trials, which are expected to begin as soon as 2021.
However, challenges remain. Although scientists are using heart cells derived from human pluripotent stem cells as effective platforms for regeneration, disease modeling, and drug screening, there is room for improvement. Stem cell-derived cardiomyocytes tend to be morphologically and functionally immature compared to their natural adult counterparts. For example, the lab-grown heart cells beat spontaneously, like pacemaker cells, a trait that may underlie disturbances in heart rhythm when these cells are transplanted.
Now a research team led by Dr. Chuck Murry at ISCRM, has shown that adding the right combination of fatty acids to a culture of stem cell-derived cardiomyocytes promotes the maturity of the heart cells, leading to the increased contractile force required for more complete recovery from heart attacks. The findings were detailed recently in a paper co-authored by Xiulan Yang, PhD and published in the journal Stem Cell Reports.
The rationale for the approach is rooted in nature. During the early stages of human development, cardiomyocytes primarily metabolize glucose before shifting to fatty acids as a main source of nutrients. In the study, the ISCRM investigators generated a medium supplement of the three fatty acids that are most abundant in breast milk and added them to stem cell-derived heart cells.
“Cardiomyocyte maturation is a hot topic right now but the metabolism aspect of it is a relatively less explored area,” says Xiulan Yang, a Research Scientist in the Murry Lab, and a lead author of the study. “We hope this research helps the field move forward, not just for cell transplantation, but for disease modeling and drug discovery too.”
Like most ISCRM investigations, the fatty acid study was a cross-lab collaboration. The Ruohola-Baker Lab assisted with the measurement of oxygen consumption rate (a key metric of metabolic rates), while the Sniadecki Lab helped the research team measure the contractile force of the cardiomyocytes. Other key contributors include ISCRM faculty members Yuliang Wang, PhD, who provided RNA sequencing analysis, Haodong Xu, PhD, whose lab helped with electrophysiological studies and Rong Tian, PhD, whose lab supported fatty acid production.
The discovery of a method to promote the maturation of heart cells has significant implications in heart regeneration, disease modeling, and drug screening. The research team is now building on the recent findings by exploring how best to combine the fatty acid cocktail with other approaches, including hormone treatment, tissue engineering, and other metabolic regulators.
This work was supported by the NationalInstitutes of Health grants R01HL146868, R01HL128362,R01HL128368, U54DK107979, P01HL094374 (all to C.E.M.),P01GM081619 (to C.E.M. and H.R.-B.), and a grant from the Fon-dation Leducq Transatlantic Network of Excellence (to C.E.M.).X.Y. was supported by the American Heart Association post-doctoral scholarship 12POST11940060 and 14POST20310023.M.L.R. was supported by an NSF Graduate Research Fellowship2011126228. J.R. was supported by a post-doctoral fellowshipfrom German Research Foundation (DFG) RI 2764/1-1. N.J.S. hasan NSF CAREER award CMMI-0846780. R.T. is supported by theNational Institutes of Health grant R01HL129510.