Cell based dATP delivery as a therapy for chronic heart failure

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

doi:10.1101/2023.04.24.538108

Cell based dATP delivery as a therapy for chronic heart failure

bioRxiv [Preprint]. 2023 Apr 28:2023.04.24.538108. doi: 10.1101/2023.04.24.538108.

Authors

Ketaki N Mhatre^{1

2

3}, Julie Mathieu^{1

4}, Amy Martinson^{1

5

3}, Galina Flint^{2

6}, Leslie P Blakley^{1

5

3}, Arash Tabesh^{1

3}, Hans Reinecke^{1

5

3}, Xiulan Yang^{1

5

3}, Xuan Guan², Eesha Murali^{1

2}, Jordan M Klaiman^{1

5

3}, Guy L Odom^{1

5

6

7}, Mary Beth Brown^{6

8}, Rong Tian^{9

6

10}, Stephen D Hauschka^{1

6

11}, Daniel Raftery^{9

10

12}, Farid Moussavi-Harami^{1

5

3

6

13}, Michael Regnier^{1

2

5

6

14}, Charles E Murry^{1

2

5

3

6

13}

Affiliations

¹ Institute for Stem Cell and Regenerative Medicine, University of Washington; Seattle, WA 98109, USA.
² Department of Bioengineering, University of Washington; Seattle, WA 98195, USA.
³ Department of Laboratory Medicine & Pathology, University of Washington; Seattle, WA 98195, USA.
⁴ Department of Comparative Medicine, University of Washington; Seattle, WA 98195, USA.
⁵ Center for Cardiovascular Biology, University of Washington; Seattle, WA 98109, USA.
⁶ Center for Translational Muscle Research, University of Washington; Seattle, WA 98109, USA.
⁷ Department of Neurology, University of Washington; Seattle, WA 98195, USA.
⁸ Division of Physical Therapy, Department of Rehabilitation Medicine, University of Washington; Seattle, WA 98195, USA.
⁹ Department of Anesthesiology and Pain Medicine, University of Washington; Seattle, WA 98195, USA.
¹⁰ The Mitochondria and Metabolism Center (MMC), University of Washington; Seattle, WA 98109, USA.
¹¹ Department of Biochemistry, University of Washington; Seattle, WA 98195, USA.
¹² Northwest Metabolomics Research Center, University of Washington; Seattle, WA 98109, USA.
¹³ Division of Cardiology, University of Washington; Seattle, WA 98195, USA.
¹⁴ Department of Physiology and Biophysics, University of Washington; Seattle, WA 98195, USA.

Abstract

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.

Publication types

Preprint

Grants and funding

P30 DK017047/DK/NIDDK NIH HHS/United States