# Contribution of macrophages in the HSC niche

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $549,162

## Abstract

PROJECT SUMMARY:
Previous studies from our laboratory have suggested that CD169+ macrophages of the bone marrow (BM)
contribute to the hematopoietic stem cell (HSC) niche activity by regulating CXCL12 synthesis in stromal cells and
their retention in the BM. Preliminary results reveal two novel functions of macrophages in directly regulating the
HSC function. First, we provide evidence that macrophages are critical for HSC regeneration after genotoxic
challenge via the regulation of iron availability mediated by signals from the gut microbiota. Second, we have
found that BM macrophages can transfer to HSCs/progenitors key retention signals that confer residence in BM.
Indeed, HSCs that have received the transfer from macrophages are retained in the BM, whereas only those that
have not are mobilized from the BM microenvironment following G-CSF administration. These results raise
important new questions as to whether the various functions of macrophages in regulating HSCs, RBC
production, or clearance are achieved by the same cells or whether the BM macrophages have specialized
functions. In this proposal, we will explore the hypothesis that macrophage can directly contribute to niche
activities by regulating HSCs’ ability to regenerate and to egress from the BM. In Specific Aim 1, we will
investigate how macrophages interact with the microbiota to promote HSC regeneration. We will use genetic
models to manipulate iron delivery pathways in HSCs and macrophages to dissect the mechanism by which iron
is supplied to HSCs/progenitors during hematopoietic regeneration. We will also evaluate how BM macrophages
can sense signals from the microbiota. In Specific Aim 2, we will investigate the mechanisms by which
macrophages assign bone marrow residence. We will assess the role of connexins in the cell-cell communication
using CRISPR/Cas9-mediated targeting and determine the role of trogocytosis as transfer mechanism. In Specific
Aim 3, we will further define the bone marrow-resident macrophage population. We will evaluate the spatial
relationship of these macrophages with vascular structures, HSCs and erythroblasts using immunofluorescence
imaging. We will investigate the origin (embryonic or hematopoietic) of BM- resident macrophages using genetic
tracing methods. These studies will shed light into the critical functions of an under-appreciated component of the
HSC niche and uncover new therapeutic approaches for blood disorders.

## Key facts

- **NIH application ID:** 10791876
- **Project number:** 5R01HL157948-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Ulrich Steidl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $549,162
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791876

## Citation

> US National Institutes of Health, RePORTER application 10791876, Contribution of macrophages in the HSC niche (5R01HL157948-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10791876. Licensed CC0.

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