# Metabolic and Transcriptional Reprogramming of Cardiac Maturation

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $605,317

## Abstract

Project Summary
Recent advances in stem cell science have led to accelerated progress in cardiac regeneration. Our group
successfully achieved large-scale re-muscularization of the infarcted hearts of macaque monkeys by
transplanting human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs). These cardiomyocytes
restored ejection from ~40% to ~62%, the largest restoration of cardiac function of which we are aware. This
therapy is complicated by the appearance of transient ventricular arrhythmias, which last for several weeks
before disappearing. Our electrophysiological studies indicate that the arrhythmias result from pacemaking
activity, which in turn results from the immaturity of the hPSC-CMs at the time of transplantation. The main
goal of this proposal is to enhance the maturation of hPSC-CM to make them non-arrhythmogenic, using
metabolic and transcriptional reprogramming. In Aim 1 we build on our observations that modulating
metabolism has wide-ranging effects on maturation, including reducing automaticity, and increasing
physiological hypertrophy, force production, and more adult-like calcium cycling. The most powerful metabolic
interventions, substrate switching, metabolic hormones, and energy sensing, will be systematically optimized to
enhance electrical maturity in vitro. Once optimized, we will explore the underlying mechanisms, and then test
whether this maturation reduces arrhythmias by transplanting them into porcine hearts. Aim 2 takes advantage
of a recently generated resource, where we performed RNA-seq on a timed series of human myocardial grafts
in the rat heart as they matured to adult levels in vivo. By comparing these data to immature cardiomyocytes,
we identified a set of transcriptional regulators that are candidate drivers of maturation. We will perform
CRISPR-based gain-of-function studies to activate these factors in vitro. Using gene expression and
electrophysiology analyses, we will then identify optimal combinations to enhance maturation. If successful,
these studies will solve the greatest barrier to stem cell-based heart regeneration and bring us much closer to
clinical trials.

## Key facts

- **NIH application ID:** 11233799
- **Project number:** 7R01HL148081-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Charles E Murry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,317
- **Award type:** 7
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11233799

## Citation

> US National Institutes of Health, RePORTER application 11233799, Metabolic and Transcriptional Reprogramming of Cardiac Maturation (7R01HL148081-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11233799. Licensed CC0.

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