# Characterizing Novel Neural Crest Derived Regulators of Hematopoietic Stem Cell Specification

> **NIH NIH R00** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $249,000

## Abstract

Project Summary
Hematopoietic stem cells (HSCs) generate all blood lineages throughout the life of an organism and are clinically
important as the therapeutic agents of bone marrow transplants used to treat hematological disorders. However,
the availability of transplant therapy is limited by difficulty in finding immunologically compatible donors. The
ability to generate large numbers of autologous HSCs in vitro from induced pluripotent stem cells (iPSCs) is a
major biomedical objective and has the potential to eliminate problems of cell availability. To date, it has not
been possible to generate bona fide HSCs with high engraftment potential and multi-lineage reconstitution. One
possible means of generating HSCs from iPSCs would be to reconstitute the full set of HSC specification signals
in vitro, however identifying these signals requires further interrogation of the molecular mechanisms controlling
HSC specification in vivo. In vertebrate embryos, HSCs arise from hemogenic endothelium (HE) lining the ventral
floor of the embryonic dorsal aorta (DA). My work using the zebrafish model of developmental hematopoiesis
has shown that trunk neural crest (NC) cells provide required inductive cues for HSC specification to the HE. To
identify novel NC derived regulators of HSC specification with the goal of informing efforts to generate HSCs in
vitro, I conducted a transcriptional profiling screen of trunk NC and endothelial cells. Using NC specific targeted
deletion of genes in zebrafish embryos, I will determine the molecular mechanisms by which candidates identified
in the screen instruct HSC specification. Additionally, I have identified the HE expressed G-protein coupled
receptor Gpr182 and putative co-receptor Ramp2, as novel regulators of HSC specification. Importantly,
knockdown of either gpr182 or ramp2 directly phenocopy the effect of NC ablation on HSC specification,
suggesting that Gpr182 could mediating a NC derived HSC specification signal. Using targeted knock out and
proteomics, I will characterize Gpr182 and Ramp2 in the control of HSC specification. Derivatives of trunk NC,
specifically sympathetic neurons and mesenchymal stem cells, control mobilization of adult HSCs. The
requirement for NC derivatives in HSC specification suggests a lifelong signaling relationship between these cell
types. I will employ permanent lineage tracing approaches to determine if HSC specification and the control adult
HSC mobilization require the same types of NC derivatives. The mentored phase of this proposal will occur at
St. Jude Children’s Research Hospital, under Dr. Wilson Clements and will confirm candidate regulators of HSC
specification and focus on generation of mutant/transgenic zebrafish lines for the independent phase. The
independent phase will elucidate the molecular mechanisms by which novel regulators instruct HSC specification
and on permanent lineage tracing of NC derivatives. The institutional resources and academic environment and
th...

## Key facts

- **NIH application ID:** 10058881
- **Project number:** 4R00DK118253-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Erich William Damm
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2018-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058881

## Citation

> US National Institutes of Health, RePORTER application 10058881, Characterizing Novel Neural Crest Derived Regulators of Hematopoietic Stem Cell Specification (4R00DK118253-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10058881. Licensed CC0.

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