Mhatre KN, Mathieu J, Martinson A, Flint G, Blakley LP, Tabesh A, Reinecke H, Yang X, Guan X, Murali E, Klaiman JM, Odom GL, Brown MB, Tian R, Hauschka SD, Raftery D, Moussavi-Harami F, Regnier M, and Murry CE
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., Competing Interests: Competing interests: M.R., C.E.M., K.N.M., and S.D.H. are inventors (University of Washington) on a patent for (US Utility Patent application # PCT/US2023/062377 filed on 10th February 2023). Some of these studies were performed while C.E.M. was an employee of Sana Biotechnology; C.E.M. is also an equity holder in Sana Biotechnology. S.D.H. has a pending patent regarding CK8m promoter. Authors declare that they have no competing interests.