Abstract
AbstractTransplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2’-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production. In vivo, dATP-producing CMs formed new myocardium that transferred dATP to host cardiomyocytes via gap junctions, increasing their dATP levels. Strikingly, when transplanted into chronically infarcted hearts, dATP-producing grafts increased left ventricular function, whereas heart failure worsened with wild-type grafts or vehicle injections. dATP-donor cells recipients had greater voluntary exercise, improved cardiac metabolism, reduced pulmonary congestion and pathological cardiac hypertrophy, and improved survival. This combination of remuscularization plus enhanced host contractility offers a novel approach to treating the chronically failing heart.One Sentence SummaryTransplanting gene-edited dATP-donor cardiomyocytes in chronically infarcted heart restores their cardiac function, improving both exercise tolerance and survival.
Publisher
Cold Spring Harbor Laboratory
Reference42 articles.
1. Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
2. Hallmarks of cardiac regeneration
3. Advanced Heart Failure: Epidemiology, Diagnosis, and Therapeutic Approaches;JACC Hear. Fail,2020
4. Cardiac donation after circulatory death: A time to reflect;Lancet,2015
5. A Study of iPS Cell-derived Cardiomyocyte Spheroids (HS-001) in Patients With Heart Failure (LAPiS Study) (LAPiS) (2021), (available at https://www.clinicaltrials.gov/ct2/show/NCT04945018).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献