# Defining the spatio-temporal mechanisms of ventricular cell specification and differentiation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $421,237

## Abstract

PROJECT SUMMARY
There currently exists a fundamental gap in our understanding of the mechanisms that underlie the
specification of cardiovascular subtypes, such as atrial and ventricular cardiomyocytes, epicardium,
endothelium smooth muscle cells during development. This represents an important problem because it
prevents the complete comprehension, and therefore also the treatment of congenital heart disease, which
affects ~1% of newborns. Importantly, this knowledge gap hinders the translational approach of generating
defined cardiovascular cell types from human pluripotent stem cells (hPSCs) based on the concept of
reproducing known principles of normal development in culture.
 The long-term goal of our work is to better understand the underlying mechanisms directing specification
and differentiation of the cardiovascular lineages. The overall objective of this application is to identify the
specific mechanisms that determine ventricular cell fate specification and differentiation during mouse
development in vivo and to translate these insights to the hPSC differentiation system to efficiently generate
human ventricular cardiomyocytes in vitro. The central hypothesis is that ventricular progenitor cells can
be identified, isolated and characterized early during development, by lineage-tracing of Foxa2, and
that this progenitor population can be reproduced during hPSC differentiations. This hypothesis has
been formulated based on preliminary data produced in the applicant's laboratory, demonstrating that
prospective ventricular cells can be identified as early as during gastrulation, using Foxa2 as a marker. Foxa2
expression and subsequent lineage-tracing enable monitoring of these cells over the course of their
specification and differentiation. In Aim 1, prospective ventricular cells will be isolated and analyzed
molecularly at key stages during development to identify the relevant signaling pathways and gene regulatory
mechanisms responsible for ventricular specification and differentiation. In Aim 2, the hPSC model system will
be used, along with ventricular-specific reporter cell lines, cell surface antibody screening technology, and
small molecule pathway modulations to establish robust protocols for the generation and characterization of
pure human ventricular cardiomyocytes.
 This approach effectively combines complementary model systems to examine specification mechanisms of
ventricular cells during heart development. We expect results from our studies to advance the understanding
of heart development by uncovering key regulators of early cardiac specification. Ultimately, such
knowledge has the potential to have a broad translational impact in the understanding of congenital heart
disease, and for the generation of therapeutically relevant and safe cell populations from hPSCs.

## Key facts

- **NIH application ID:** 10103837
- **Project number:** 5R01HL134956-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Nicole Dubois
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $421,237
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103837

## Citation

> US National Institutes of Health, RePORTER application 10103837, Defining the spatio-temporal mechanisms of ventricular cell specification and differentiation (5R01HL134956-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10103837. Licensed CC0.

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