# Mechanisms of Cell-Based Heart Regeneration

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $871,202

## Abstract

Project Summary
Recent studies from our group demonstrate that human embryonic stem cell-derived cardiomyocytes (hESC-
CM) can improve the function of infarcted hearts of macaque monkeys. These improvements of as much as
20 ejection fraction points are associated with robust remuscularization, often giving centimeter-scale grafts
that are visible by MRI. As we progress toward clinical trials, however, several outstanding questions remain
unanswered. What is the mechanism of hESC-CM action? How can the relatively low efficiency of cardiac
engraftment be improved? Will we get more complete regeneration if we add key myocardial cell types in
addition to cardiomyocytes? In Aim 1 we address whether the mechanism of hESC-CM action is related to
direct cell replacement, or if there is a significant paracrine component. To test this, we have used CRISPR-
Cas9 to delete cardiac and skeletal TNNI genes in hiPSCs, yielding non-contractile cardiomyocytes with intact
myofibrils, action potentials and calcium transients. These “paracrine-only” cardiomyocytes will be compared
to wild type cells for their ability to repair the infarcted rat heart. In Aim 2 we will test the hypothesis that a
“smart hydrogel”, designed to signal through the Notch pathway, can improve cardiac regeneration with hiPSC-
CMs. This Notch gel stimulates hiPSC-CM proliferation after engraftment and promotes vascular ingrowth
from the surrounding host microcirculation. We will test if these structural benefits are accompanied by
enhanced ventricular function. Finally, Aim 3 follows up on recently completed studies in the rat, where we
observed that hESC-derived epicardial cells (hESC-Epi) are synergistic with hESC-CMs in terms of promoting
enhanced remuscularization and functional recovery of the infarcted heart. We will utilize our macaque
monkey model to test whether hESC-Epi augment hESC-CM-based heart regeneration, with the hypothesis
that these cells will promote hESC-CM maturation and enhance their proliferation, resulting in less arrhythmogenic
grafts that more completely remuscularize the infarct. Studies in this proposal will impact directly on our
upcoming clinical trials of cardiac repair.

## Key facts

- **NIH application ID:** 10124432
- **Project number:** 5R01HL146868-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Charles E Murry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $871,202
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124432

## Citation

> US National Institutes of Health, RePORTER application 10124432, Mechanisms of Cell-Based Heart Regeneration (5R01HL146868-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124432. Licensed CC0.

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