# Estrogen Receptor Signaling in Hematopoietic Stem Cell Proliferation and Mobilization

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $360,800

## Abstract

PROJECT SUMMARY
Mobilization of hematopoietic stem cells (HSCs) into the peripheral blood is widely used in clinical HSC
transplantation to treat many blood disorders. However, the HSC supply is not sufficient and a considerable
number of healthy donors and patients fail to mobilize HSCs via the standard mobilization protocol. Thus,
improved strategies for inducing HSC mobilization and promoting hematopoietic repopulation after
transplantation by inducing HSC proliferation are needed to improve patient outcomes. Although acute
hematopoietic demands promote HSC proliferation and mobilization, little is known about the molecular
mechanisms. To better understand how these HSC behaviors are regulated, we have used pregnancy in mice
as a model system. We previously found that HSC proliferation, mobilization, and extramedullary hematopoiesis
are induced during pregnancy when maternal blood volume expands rapidly. These responses are dependent
on HSC expression of estrogen receptor α (ERα). Signaling through this nuclear hormone receptor can be
triggered by 17β-estradiol (E2) as well as 27-hydroxycholesterol (27HC), the endogenous ER ligand that is a
direct metabolite of cholesterol. Importantly, different ER ligands have different effects on ER function, leading
to differential effects on gene expression. Given our finding that ERα ligands differentially induce HSC
proliferation and mobilization, we hypothesize that administration of ERα ligands and modulation of specific
genes downstream of ERα signaling could be used to improve collection of mobilized HSCs for transplantation
as well as hematopoietic repopulation after transplantation. To test this hypothesis, we propose the following
Aims. In Aim 1, we will determine the potential of 27HC-ERα signaling to improve current HSC-mobilizing
methods. In conjunction with clinically-used HSC-mobilizing agents, we will administer 27HC to wild-type mice
or mice with humanized hematopoietic systems, and evaluate the levels of mobilized mouse and human HSCs.
In Aim 2, we will determine the potential of E2-ERα signaling to enhance hematopoietic repopulation after
transplantation. We will transplant mouse or human HSCs to recipient mice and treat these recipient mice with
E2 to induce HSC proliferation. We will evaluate whether the treatment has beneficial effects on HSC proliferation
and hematopoietic repopulation by increasing hematopoietic progenitors after transplantation. In Aim 3, we
propose to identify key effector genes of ERα-mediated induction of HSC proliferation and mobilization. We will
select candidate genes by comparing gene expression profiles of HSCs in mice that have either upregulated or
downregulated 27HC-ERα signaling or E2-ERα signaling. We will functionally validate their roles in HSC
proliferation and mobilization in vivo by lentiviral transduction. Successful completion of this study will shed light
on the molecular mechanisms of HSC proliferation and mobilization, and will lay the ground...

## Key facts

- **NIH application ID:** 10033689
- **Project number:** 1R01DK125747-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Hideyuki Oguro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,800
- **Award type:** 1
- **Project period:** 2020-08-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033689

## Citation

> US National Institutes of Health, RePORTER application 10033689, Estrogen Receptor Signaling in Hematopoietic Stem Cell Proliferation and Mobilization (1R01DK125747-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10033689. Licensed CC0.

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