# Mechanisms that regulate erythroid differentiation of hematopoietic stem cells

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $86,400

## Abstract

Hematopoietic stem cells (HSCs) are capable of regenerating the entire hematopoietic system. This capacity is
fully unleashed upon bone marrow transplantation, however, recent studies including ours indicate that HSCs
have a much more limited contribution to hematopoiesis during homeostasis. While stress from sources like
chemotherapies or inflammation increases the contribution from HSCs to multiple hematopoietic lineages, little
is known about how HSCs respond to stressors that cause anemia. Identifying the progenitor cell population and
signals that promote erythroid regeneration may lead to novel strategies to better harness HSCs for the treatment
of anemia and regenerative medicine overall. Using a HSC lineage tracing model, we found that hemolytic
anemia specifically enhances erythroid contribution by HSCs, indicating that HSCs respond to erythroid stress
by initiating erythropoiesis. After hemolytic anemia, HSCs expressed more erythropoiesis-related genes and
exhibited enhanced erythroid differentiation in vitro and in vivo. Interestingly, HSCs had increased iron content
after hemolytic anemia and iron chelation prevented erythroid-biased differentiation. Iron is a cofactor for the
iron(II)/α-ketoglutarate-dependent dioxygenase TET2 that demethylates DNA, and erythropoiesis is associated
with DNA demethylation. We found that TET2 protein, but not mRNA, is increased in HSCs during anemia and
deletion of Tet2 suppressed the enhanced erythroid differentiation of HSCs we observed following hemolytic
anemia. We thus hypothesized that HSCs respond to anemia by increasing iron uptake, TET2 expression, and
DNA demethylation, thereby increasing the expression of erythropoiesis genes. In Aim 1, we will study the
heterogeneity of splenic HSCs during anemia and identify the erythroid-biased fraction of HSCs. In Aim 2, we
will examine the role of TET2 in promoting erythroid commitment of splenic HSC. In Aim 3, we will investigate
the mechanism by which TET2 protein is stabilized in HSCs during anemia. Completion of this study will provide
novel insights into the differences between bone marrow and splenic HSCs in responding to anemia, and the
mechanism by which iron and TET2 instructs HSCs to become committed to the erythroid lineage.

## Key facts

- **NIH application ID:** 11029945
- **Project number:** 3R01HL165145-03S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daisuke Nakada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,400
- **Award type:** 3
- **Project period:** 2024-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11029945

## Citation

> US National Institutes of Health, RePORTER application 11029945, Mechanisms that regulate erythroid differentiation of hematopoietic stem cells (3R01HL165145-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11029945. Licensed CC0.

---

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