| Autor: |
Ketaki N Mhatre, Julie Mathieu, Amy Martinson, Galina Flint, Leslie P. Blakley, Arash Tabesh, Hans Reinecke, Xiulan Yang, Xuan Guan, Eesha Murali, Jordan M Klaiman, Guy L Odom, Mary Beth Brown, Rong Tian, Stephen D Hauschka, Daniel Raftery, Farid Moussavi-Harami, Michael Regnier, Charles E Murry |
| Rok vydání: |
2023 |
| Popis: |
Transplanted 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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