# Mesodermal Commitment of the Definitive Hematopoietic Program

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $422,500

## Abstract

PROJECT SUMMARY / ABSTRACT
The overall goal of our research is to understand the origin, development and regulation of the embryonic
progenitor to the hematopoietic stem cell (HSC), hemogenic endothelium (HE). The focus of this proposal is to
use human pluripotent stem cells (hPSCs) and mouse embryonic development as complementary model
systems to identify the essential signals and genes for HE specification. Currently, the signal requirement(s) for
HE specification from nascent mesoderm during embryonic development remains a poorly understood process.
Our proposed studies build on our recent advances in the directed differentiation of definitive hematopoietic
progenitors from hPSCs, having identified a WNT-dependent mesodermal population that harbors exclusively
definitive hematopoietic potential, via CDX4 expression. We have now identified a novel subset of early
mesoderm that is entirely dependent on retinoic acid (RA) signaling for the generation of HOXA+ HE with multi-
lineage definitive hematopoietic potential. As RA is required for HE function during embryogenesis, we
hypothesize that hPSC-derived RA-dependent HE is derived from a very unique mesodermal subset, which is
ontogenically distinct from mesoderm harboring HSC-independent HE potential. We will test this hypothesis
across 3 Specific Aims. In Aim 1, we will assess the physiological relevance of ALDH1A2+ derived HE, both in
vitro and in vivo. The objective of these studies is to understand whether ALDH1A2+ mesoderm gives rise to
HSC-competent HE. In Aim 2, we will define the mechanism the specification of RA-dependent HE. The objective
of these studies is to determine how RA signaling affects HE development. In Aim 3, we will identify the role of
alternative splicing during RA-dependent definitive hematopoietic specification. The objective of these studies is
to define the essential transcriptional regulators within early mesoderm for the development of HE. The
successful completion of these studies will provide us with a more comprehensive understanding of
hematopoietic development. This is of fundamental importance to basic biology, and the insights generated from
these studies will have clinical implications, such as the in vitro generation of HSCs for a wide array of
regenerative medicine applications. Our unique cellular and molecular tools, combined with our expertise in
hematopoietic development, stem cell biology and bioinformatics puts us in an ideal position to make a significant
impact in this field.

## Key facts

- **NIH application ID:** 10415008
- **Project number:** 5R01HL145290-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Christopher Michael Sturgeon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,500
- **Award type:** 5
- **Project period:** 2021-01-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415008

## Citation

> US National Institutes of Health, RePORTER application 10415008, Mesodermal Commitment of the Definitive Hematopoietic Program (5R01HL145290-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10415008. Licensed CC0.

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