# Reprogramming of hematopoietic stem cells during contact with the perivascular niche

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $493,810

## Abstract

PROJECT SUMMARY/ABSTRACT
Hematopoietic stem and progenitor cell (HSPC) transplantation is a curative treatment for many blood diseases
and cancers. However, these procedures still need to be optimized to improve patient outcomes and survival.
HSPCs reside in a microenvironment surrounded by niche cells that help regulate their function. Our research
proposal seeks to address fundamental questions regarding the cellular interactions between HSPCs and niche
cells. During development in the embryo, HSPCs move through different tissues and have changing
requirements for contact with the microenvironment. HSPCs first arise in the dorsal aorta, a large vessel in the
embryo, and are then released into circulation. Next, HSPCs migrate to the fetal liver where the population of
cells expands via symmetric divisions. Finally, HSPCs migrate again to colonize the bone marrow where they
will remain throughout adulthood. As HSPCs are migrating between these different hematopoietic tissues, they
are also becoming more mature and are programmed towards their adult quiescent state. We use zebrafish and
mice as model systems that are highly conserved with humans and have many genetic tools for functional testing
and live imaging of cellular behaviors. In zebrafish, we have found a novel role for vascular endothelial growth
factor c (vegfc) in the release of HSPCs from the dorsal aorta. Vegfc also regulates a fate decision in pre-HSPCs
that determines if they will become a stem cell or a different type of progenitor cell. At later stages, we found that
integrin alpha 4 (itga4) in the caudal hematopoietic tissue (CHT), the zebrafish equivalent of the fetal liver, is
required for proper epigenetic programming of HSPCs. We hypothesize that dissecting niche-dependent HSPC
programming, using mutants with prolonged or shortened retention in developmental niches, will enable us to
decode mechanisms governing HSPC fate decisions and track their long-term impact on hematopoiesis. We will
address this hypothesis through the following Specific Aims: 1) Determine the role of vegfc in fate
determination and release of HSPCs from the hemogenic endothelium of the dorsal aorta; 2) Establish
how itga4-dependent contact with the fetal/CHT niche programs HSPCs as they transition from immature
to mature states. We will perform in vivo genetic knockdown and small molecule treatments, together with live
imaging, to understand the dynamic interactions between HSPCs and niche cells. We will use a multiomics
approach to infer and functionally test the gene regulatory networks involved in HSPC programming. Together,
our proposed aims will identify functionally critical signals and networks that integrate to program HSPCs. Our
goal is for these novel insights and paradigms to improve HSPC-based therapies for patients.

## Key facts

- **NIH application ID:** 10943341
- **Project number:** 1R01HL174965-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Owen James Tamplin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $493,810
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943341

## Citation

> US National Institutes of Health, RePORTER application 10943341, Reprogramming of hematopoietic stem cells during contact with the perivascular niche (1R01HL174965-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10943341. Licensed CC0.

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