# Inflammatory modulation of CXCL12 expressing niche cells in bone marrow

> **NIH NIH P01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $511,746

## Abstract

PROJECT SUMMARY
Acute inflammatory signals associated with infection lead to HSC proliferation thus generating large numbers
of immune effector cells. However, more severe and prolonged inflammation has been linked to bone marrow
failure states, e.g. complications following bone marrow transplantation. Infectious as well as non-infectious
inflammatory signals affect HSC homeostasis. Such effects can be mediated directly on HSC or indirectly via
niche cells. CXCL12-expressing niche cells represent an important niche cell population forming distinct niches
that support hematopoietic stem and/or progenitor cells. Utilizing complementary novel imaging approaches for
2D and 3D analysis of the bone marrow cavity, we show that inflammatory stress following administration of
TNF-α and/or lipopolysaccharide (LPS) rapidly reduces the number of CXCL12 expressing niche cells and
causes defects in niche cell cytoplasmic structure within 1-4 hours. We propose that understanding how
inflammatory signals modulate HSCP niche cells may implicate a pathogenic role of niche cells in disorders of
dysfunctional hematopoiesis associated with inflammation in the peri-transplant setting. In Aim 1 we will
delineate the consequences of inflammation on CXCL12-niche cell number and/or growth factor expression in
specific CXCL12 expressing niche cell populations. The analyses will be done at various time intervals
following administration of TNF-α, LPS. In aim 2, the dynamic alterations in CXCL12 expressing niche cell
cytoplasmic structure will be visualized and quantified at different time intervals by three complementary
imaging techniques. The dynamic structural changes will be correlated with hematopoietic cellularity in BM and
egress into the circulation. In aim 3, we will examine whether LPS and TNF-α mediate their effect on
hematopoiesis directly or indirectly (e.g. by acting first on hematopoietic cells such as macrophages). To this
end, 4 separate reconstituted chimeric mice in which the hematopoietic compartment/bone marrow
microenvironment is either WT or deficient in TNFR/TLR4, will be generated. We propose that understanding
the dynamic relationship between stromal cells and HSPC following inflammatory stress may lead to new
therapeutic approaches for hematopoietic regeneration in bone marrow dysfunction states in the peri-
transplant setting, which require significant blood product support.

## Key facts

- **NIH application ID:** 9897590
- **Project number:** 5P01HL095489-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Leslie Eric Silberstein
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,746
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897590

## Citation

> US National Institutes of Health, RePORTER application 9897590, Inflammatory modulation of CXCL12 expressing niche cells in bone marrow (5P01HL095489-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897590. Licensed CC0.

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