# Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $552,416

## Abstract

ABSTRACT
 Human embryonic stem cells (hESCs) can be an unlimited source for generation of cardiovascular cells at
different stages of their development. The ultimate goal of cardiac stem cell therapy is to deliver therapeutically
relevant cells to damaged hearts that can repopulate the injury area, electromechanically couple with the host
myocardium, and provide functional benefit. However, the clinical application of hESC-based cell therapy is
limited by many technical challenges including the inability to deliver a pure population of cardiomyocytes that
can functionally integrate into the host myocardium without the risk of arrhythmias. Additionally, lack of
appropriate large animal models with clinically relevant injury prototype has limited our understanding of the fate
of hESC-derived cells after transplantation.
 Attempts to date for delivery of hESC-derived cardiac cells has relied on differentiation protocols that result
in beating cells in a dish, which are considered cardiomyocytes for transplantation. However, their impurity, which
may include cardiomyocyte subtypes such as pacemaker cells, may lead to serious safety issues, such as
arrhythmias. Therefore, isolation of a pure population left ventricular (LV) cardiomyocytes that closely resemble
the endogenous cardiomyocytes is an important goal of cell-based therapy. Recently, we isolated and
characterized first- and second-heart filed cardiomyocytes, as well as pacemaker cells from differentiating
hESCs. Additionally, with our computational biologist collaborator, we reported how cardiovascular progenitors
make fate decisions during development. And finally, our group established the first large animal facility at UCLA
where we have performed hESC-derived transplantation in porcine infarct hearts. We believe the expertise and
experience of our group along with the available resources will contribute to the success of the proposed project.
 We hypothesize that hESC-derived LV cardiomyocytes can engraft into the host myocardium and provide
functional benefit. In specific aim 1, we plan to isolate LV cardiomyocytes from differentiating hESCs by
modifying Activin/Nodal and retinoic acid signaling pathway. We will fully characterize these cells based on their
gene and protein expression, as well as electrophysiology at a single cell level. In specific aim 2, by analyzing
single cell gene expression profile of hESC-derived and endogenous cardiomyocytes at different stages of
development, we plan to explore the molecular signatures that mediate differentiation and maturation in vitro.
And finally, in specific aim 3, we propose to transplant hESC-derived LV cardiomyocytes in a clinically relevant
model of a porcine myocardial infarction. We will perform invasive and non-invasive tests to determine structural
and functional integration of the transplanted cells into the host myocardium. We believe that the success of this
project will enhance our understanding of hESC differentiation and matur...

## Key facts

- **NIH application ID:** 9971562
- **Project number:** 5R01HL148714-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Reza Ardehali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $552,416
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971562

## Citation

> US National Institutes of Health, RePORTER application 9971562, Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model (5R01HL148714-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971562. Licensed CC0.

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