# An integrated human stem cell model for elucidating myocardial-endocardial interactions in cardiac development and disease

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2021 · $385,000

## Abstract

Hypoplastic left heart syndrome (HLHS) is a severe type of congenital heart defects, which is characterized
by the underdevelopment of left side of the heart. The clinical presentation of HLHS includes hypoplasia of the
left ventricle and structural defects in mitral valves, aortic valve, and ascending aorta. HLHS newborns usually
die within a week without surgical treatment. We and others have linked the pathogenic NOTCH1 mutations to
HLHS and calcific aortic valve disease. It appears that abnormal NOTCH signaling interrupts the communication
between myocardium and endocardium thus leads to incomplete growth of ventricular chamber. However, the
mechanisms by which NOTCH1 mutations results in hypoplasia of the left ventricle are largely unknown due to
limited models for studying HLHS. Genetically engineered animals are not capable of reproducing the clinical
phenotypes in HLHS patients. Previous studies have focused on the structural and electrophysiological defects
in cardiomyocytes from HLHS patient-derived induced pluripotent stem cells (iPSCs), which may not recapitulate
the underlying non-cell autonomous scenarios in the hypoplastic ventricles. In this proposal, we hypothesize that
NOTCH1-mediated myocardial-endocardial crosstalk is required for normal human ventricular cardiomyocyte
differentiation, and NOTCH1 mutations leads to abnormal myocardial-endocardial interactions which cause the
hypoplasia of ventricular cardiomyocytes in HLHS. We will employ an integrated stem cell model using HLHS
and CRISPR genome-edited iPSCs to investigate how NOTCH1 mutations lead to abnormal myocardial-
endocardial interactions in HLHS. We will design a novel co-culture platform using human iPSC-derived
cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) with distinct NOTCH1 genetic composition to
study the intercellular communication between endocardium and myocardium in both healthy and diseased
conditions. In Specific Aim 1, we will investigate the cellular and molecular mechanisms by which endothelial
NOTCH1 deficiency suppresses human ventricular cardiomyocyte differentiation and proliferation. In Specific
Aim 2, we will determine how the crosstalk between myocardium and endocardium affects ventricular
cardiomyocyte differentiation and proliferation by co-culture of human iPSC-CMs and iPSC-ECs. In Specific
Aim 3, we will decipher the mechanisms by which NOTCH1 mutations results in the dysfunctional myocardial-
endocardial interactions and contribute to hypoplasis of the left ventricle using genome-edited HLHS-iPSCs. The
completion of this R01 project will have a major impact on the understanding of HLHS through interactions
between endocardium and myocardium using clinically relevant and patient-derived cardiomyocytes and
endothelial cells.

## Key facts

- **NIH application ID:** 10098696
- **Project number:** 1R01HL155282-01
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Mingtao Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098696

## Citation

> US National Institutes of Health, RePORTER application 10098696, An integrated human stem cell model for elucidating myocardial-endocardial interactions in cardiac development and disease (1R01HL155282-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10098696. Licensed CC0.

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