Cell based dATP delivery as a therapy for chronic heart failure.

Autor:	Mhatre KN; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Mathieu J; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Comparative Medicine, University of Washington; Seattle, WA 98195, USA., Martinson A; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Flint G; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA., Blakley LP; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Tabesh A; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Reinecke H; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Yang X; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Guan X; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA., Murali E; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA., Klaiman JM; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA., Odom GL; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Department of Neurology, University of Washington; Seattle, WA 98195, USA., Brown MB; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Division of Physical Therapy, Department of Rehabilitation Medicine, University of Washington; Seattle, WA 98195, USA., Tian R; Department of Anesthesiology and Pain Medicine, University of Washington; Seattle, WA 98195, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; The Mitochondria and Metabolism Center (MMC), University of Washington; Seattle, WA 98109, USA., Hauschka SD; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Department of Biochemistry, University of Washington; Seattle, WA 98195, USA., Raftery D; Department of Anesthesiology and Pain Medicine, University of Washington; Seattle, WA 98195, USA.; The Mitochondria and Metabolism Center (MMC), University of Washington; Seattle, WA 98109, USA.; Northwest Metabolomics Research Center, University of Washington; Seattle, WA 98109, USA., Moussavi-Harami F; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Division of Cardiology, University of Washington; Seattle, WA 98195, USA., Regnier M; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Department of Physiology and Biophysics, University of Washington; Seattle, WA 98195, USA., Murry CE; Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington; Seattle, WA 98195, USA.; Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.; Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA.; Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.; Division of Cardiology, University of Washington; Seattle, WA 98195, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 28. Date of Electronic Publication: 2023 Apr 28.
DOI:	10.1101/2023.04.24.538108
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu