# Cellular crosstalk in the hematopoietic microenvironment

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $395,270

## Abstract

Abstract:
Our overall goal is to identify the mechanisms through which TNFα-producing hematopoietic cells regulate
blood vessels and perivascular HSPC (Hematopoietic stem and progenitor cells) vascular niches. HSPC are
responsible for generating all the cells found in the blood and are indispensable for life. HSPC reside in the
bone marrow associated with specific structures (niches) composed by different types of cells including
endothelial cells, CD45-CD31-LepR+, CD45-CD31-Ng2+ cells and megakaryocytes. These niches maintain and
regulate HSPC and are indispensable for HSC maintenance. However, little is known about the mechanisms
that regulate the different components of the niche during homeostasis and regeneration. Identifying these
mechanisms is critical to understand how HSPC are regulated in health and disease and because it might lead
to novel therapies that target the niche to treat disease.
In our preliminary studies we have discovered two entirely novel functions for TNF-producing cells in
hematopoiesis: 1) We found that bone marrow (but not peripheral) granulocytes use TNF to create a
regenerative microenvironment that promotes the expansion of the stromal niches that sustain hematopoiesis
and accelerates hematopoietic recovery after autologous transplantation in mice. Our results suggest that
manipulation of granulocytes and/or TNF signals can be used to accelerate donor cell engraftment after
transplantation. We also found, in human beta thalassemia patients, that higher numbers of granulocytes in the
initial graft predicted faster peripheral and neutrophil engraftment. This data supports the hypothesis that
granulocytes might also play a role in driving regeneration in human patients. 2) We found that TNF-
producing cells control the size of the perivascular niche and HSC localization to BM niches. Our results
demonstrate that, during homeostasis, TNF-producing cells regulate vascular niche abundance by controlling
the numbers of endothelial cells and perivascular cells in the niche. We also found that, in Tnfα-/- mice, HSC
relocate away from perivascular niches. In this proposal we investigate the mechanisms of this TNF-mediated
cellular crosstalk. In Aim 1 we will investigate the mechanisms through which granulocytes drive vascular and
hematopoietic regeneration, their function in vascular homeostasis, and whether pharmacological manipulation
of these granulocytes can be utilized to promote regeneration after myeloablation. In Aim 2 of this proposal we
will utilize chimeric mice and genetic models for Tnfrsf1a (one of the TNF receptors) reactivation and Tnfα
deletion and a 5-color immunofluorescence imaging of HSC and their niches to identify the source and targets
of TNF that regulate HSC function and localization to the niche.

## Key facts

- **NIH application ID:** 9921466
- **Project number:** 5R01HL136529-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Daniel Lucas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,270
- **Award type:** 5
- **Project period:** 2018-05-04 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921466

## Citation

> US National Institutes of Health, RePORTER application 9921466, Cellular crosstalk in the hematopoietic microenvironment (5R01HL136529-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9921466. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*