# The Metabolic Regulation of Hematopoietic Stem Cell Function

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

PROJECT SUMMARY/ABSTRACT
A fundamental question is whether physiological variations in metabolite levels in vivo influence stem cell function
or tissue regeneration. Our understanding of somatic stem cell metabolism remains limited due to the technical
challenges associated with studying metabolism in rare cells in vivo. To address this issue we optimized the
sensitivity of metabolomics methods to enable the analysis of rare cell populations. We used this approach to
compare metabolite levels between hematopoietic stem cells (HSCs) and a wide range of restricted
hematopoietic progenitors isolated from mouse bone marrow. We found that each hematopoietic stem and
progenitor cell population has a distinct metabolic signature. Human and mouse HSCs are distinguished from
most other hematopoietic cells by unusually high levels of ascorbate (vitamin C). Ascorbate depletion in mice, to
a level observed in 5% of Americans, increases HSC frequency and function, partly by reducing the activity of
Tet2, a cytosine demethylase that suppresses leukemia development. Ascorbate depletion, like Tet2 deletion,
cooperates with Flt3ITD to promote myelopoiesis and leukemogenesis. Ascorbate acts cell-autonomously to
negatively regulate HSC function and myelopoiesis mainly through Tet2-dependent mechanisms. These
observations are likely relevant to public health as plasma ascorbate levels vary widely among Americans,
largely due to dietary differences. At any one time, 13% of Americans are considered ascorbate deficient. In Aim
1, we propose to test whether ascorbate levels influence steady-state hematopoiesis or regeneration after
hematopoietic stresses. In Aim 2, we propose to test whether ascorbate depletion promotes clonal
hematopoiesis under steady state conditions or in response to hematopoietic stresses. Clonal hematopoiesis of
indeterminate potential has recently been shown to be common in healthy older people as well as in patients
with aplastic anemia, solid cancers, and patients who have received hematopoietic transplants. The presence of
clonal hematopoiesis is associated with adverse health outcomes including cardiovascular disease. Clonal
hematopoiesis is usually caused by the loss of one allele of Tet2 or by loss-of-function mutations in Dnmt3a. We
hypothesize that ascorbate depletion can promote the development and progression of clonal hematopoiesis by
reducing Tet2 function. In Aim 3 we will assess the molecular mechanisms by which ascorbate depletion and
Tet2 deficiency regulate HSC function and myelopoiesis. We expect these studies to expand our understanding
of how metabolism regulates the HSC epigenome, HSC function, normal hematopoiesis, and clonal
hematopoiesis.

## Key facts

- **NIH application ID:** 9914262
- **Project number:** 5R01DK118745-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** SEAN J MORRISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914262

## Citation

> US National Institutes of Health, RePORTER application 9914262, The Metabolic Regulation of Hematopoietic Stem Cell Function (5R01DK118745-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914262. Licensed CC0.

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