# Novel hematopoietic stem cell specification signals from the neural crest

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $403,875

## Abstract

Project Summary
Hematopoietic stem cells (HSCs) are the foundation of the adult hematopoietic system. These self-renewing
progenitors that reside in the adult bone marrow generate all mature blood lineages through life. Clinically,
HSCs are the therapeutic component of bone marrow transplants, used in the treatment of both malignant and
non-malignant blood disorders. Inconsistent availability of donors, limitations in graft material, and the possible
use of in vitro derived HSCs as a platform for gene therapy and gene editing approaches to treatment of
disease has heightened interest in directed differentiation of HSCs from pluripotent precursors, such as
induced pluripotent stem (iPS) cells. But despite decades of research, generation of true HSCs with high
efficiency engraftment and full multilineage potential remains impossible, suggesting that key specification
signals remain to be determined. An obvious means of instructing HSC specification in vitro is by attempting to
recapitulate the normal embryonic inductive processes. Across vertebrate phyla, HSCs are specified from
developing arterial endothelium, most notably in the primitive descending aorta of mammalian embryos, or its
cognate, the dorsal aorta in anamniotic vertebrates such as zebrafish. Significant progress towards generation
of the immediate precursor to HSCs, the “hemogenic endothelium”, has been made in recent years, but the full
set of inductive signals that work directly on this endothelium to initiate the definitive hematopoietic program
has not been determined. Specification signals likely come from neighboring cells that form an inductive
specification “niche.” As nothing is known about the origin or composition of such cells, we set out to define
cell types that might contribute to the specification niche. Hematopoietic programming is highly conserved from
mammals to zebrafish, and in vivo observation of tissue specification and hematopoietic development is highly
accessible in fish, due to their rapid development, optical transparency at the times when HSCs are specified,
and the availability of diverse transgenic animals in which tissue and cell types are labeled by fluorescence
transgenes. In preliminary studies with zebrafish, we have determined that neural-crest-derived cells are the
first known cell type contributing to the HSC specification niche. Our results show that neural crest cells
physically contact hemogenic endothelium shortly before the HSC program initiates. Multiple separate
perturbations causing defects in neural crest specification or morphogenesis lead to a loss of HSCs,
demonstrating that proper neural crest patterning is required for HSC specification. These data establish neural
crest cells as a key component of the inductive HSC specification niche, indicating that signals they present
are critical to instruct initiation of the hematopoietic program. Here we propose to identify the unknown HSC
specification signals presented by neural crest, and...

## Key facts

- **NIH application ID:** 9933912
- **Project number:** 5R01DK113973-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Wilson Kendrick Clements
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,875
- **Award type:** 5
- **Project period:** 2017-08-02 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933912

## Citation

> US National Institutes of Health, RePORTER application 9933912, Novel hematopoietic stem cell specification signals from the neural crest (5R01DK113973-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9933912. Licensed CC0.

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