# Hemolysis and the Hematopoietic Niche

> **NIH NIH P01** · NEW YORK BLOOD CENTER · 2024 · $737,425

## Abstract

ABSTRACT
Sickle cell disease (SCD) is a major healthcare burden with limited treatment options. Currently available
treatments are limited to transfusions, hydroxyurea and L-glutamine. With increasing interest in hematopoietic
stem cell (HSC) transplantation and gene therapy as treatment options for SCD, understanding how hemolytic
stress alters the bone marrow (BM) microenvironment is critical for the development of appropriate therapeutic
strategies. In Aim 1, we will investigate the effects of hemolysis on the BM niches including mesenchymal stem
cells (MSCs), responsible for maintaining HSCs, and erythroblastic islands (EBIs), the niche for erythropoiesis.
In Aim 2, we will define the mechanisms for the effects of hemolysis on erythroid progenitors/precursors. We
further propose to determine whether therapy with transfusion, heme scavenger hemopexin or the combination
can improve the function of MSCs and EBI macrophages. Our overall hypothesis is that free heme leads to
dysfunction of the BM hematopoietic niche and hematopoietic stem/progenitor cells, which can be alleviated in
part by hemopexin and/or transfusion therapy. First, we will investigate the effects of hemolysis on the BM MSC
ability to regulate hematopoiesis. We will evaluate numerous MSC stem cell properties and investigate how
alterations may in turn affect HSC activation state, accumulation of ROS and DNA damage. Next, we will define
the mechanisms for the impaired erythropoietic activity due to hemolysis, including mechanisms for defective
EBIs formation, CFU-E colony formation and enucleation. These studies are enabled by the SCD mouse model,
Thal mouse model, Epor-eGFP knockin mouse model, mouse models targeting BM MSCs, our recent
identification of Epor+ EBI macrophages, validation of both anti-mouse Epor and anti-human EPOR antibodies
as well as the methods we have developed to purify erythroid cells at distinct developmental stage and to quantify
both murine and human BM terminal erythroid differentiation. These studies will provide a comprehensive
mechanistic understanding of the effects of hemolysis on BM hematopoietic niches, and contribute to the
development of novel therapeutics targeting the BM niche cells and ultimately improve treatment options for
patients with SCD.

## Key facts

- **NIH application ID:** 10880428
- **Project number:** 5P01HL149626-05
- **Recipient organization:** NEW YORK BLOOD CENTER
- **Principal Investigator:** Xiuli An
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $737,425
- **Award type:** 5
- **Project period:** 2020-07-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880428

## Citation

> US National Institutes of Health, RePORTER application 10880428, Hemolysis and the Hematopoietic Niche (5P01HL149626-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10880428. Licensed CC0.

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