The long term goal of these studies is to develop a heart regeneration strategy that can be translated to humans. Our current focus is in human pluripotent stem cells, and more specifically, in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Building on 15 years' work in cell culture and small animals, we recently showed that hESC-CMs can be produced at a scale and purity that permit testing in the animal most likely to predict the human response: the non-human primate Macaca nemestrina. The hESC-CMs can generate grafts that average 40% of infarct size, and they electromechanically couple, beat in sync with the macaque heart and mature to adult size by 3 months. This proposal addresses the next-level challenges.
Aim 1 is a pivotal efficacy study that will determine if hESC-CMs enhance contractile function in the infarcted macaque heart. Three doses of human cardiomyocytes will be tested, and ventricular structure and function will be determined by MRI.
Aim 2 addresses the genesis of ventricular arrhythmias identified in our recent study. In addition to monitoring heart rhythm by telemetry, we will perform serial catheter-based mapping of the engrafted (3 cell doses) and sham-engrafted primate heart, generating activation maps that will classify arrhythmias as resulting from reentry or ectopic pacemakers. Programmed electrical stimulation will assess susceptibility to induced arrhythmias. In combination with Aim 1, these studies will determine if there is a dose of cardiomyocytes that enhances function without arrhythmias.
Aim 3 uses molecular imaging techniques to assess graft population dynamics, tracking the waves of cell death and proliferation after transplantation. We also address the key question of graft vascularization, testing the hypothesis that grafts induce host coronary arterial remodeling and that, despite this response, that grafts are chronically underperfused. These experiments will provide the foundation for a planned clinical trial of heart repair and provide mechanistic insights not possible in human patients.

Public Health Relevance

We recently demonstrated that large scale re-muscularization of the primate heart is possible and that human cardiac grafts electrically couple and beat in synchrony with the primate heart. The proposed studies will build on these observations by determining if these grafts restore cardiac pump function, by determining the electrophysiological basis for transient arrhythmias that result as the grafts heal in, and by determining whether the grafts enhance blood flow via angiogenesis and arteriogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128362-04
Application #
9654768
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2016-04-01
Project End
2020-02-28
Budget Start
2019-03-01
Budget End
2020-02-28
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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