# Inflammatory Regulation of Hematopoietic Stem and Progenitor Cells to Enhance Innate Immunity

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $398,609

## Abstract

Project Summary / Abstract
Neutropenia, a deficiency in certain white blood cells, is a common side effect of chemotherapy that exposes
patients to a high risk of death from opportunistic infections. Existing methods to restore neutrophils, including
G-CSF administration and granulocyte infusions, have not produced a clear improvement in outcome, and new
approaches are needed. White blood cells are the product of bone marrow hematopoietic stem and progenitor
cells (HSPCs) that can be triggered to divide and differentiate by circulating inflammatory signals. Our prior
work shows that the inflammatory cytokine interferon gamma (IFNg) is a potent stimulus for hematopoietic
stem cell (HSC) division and myeloid differentiation. Yet persistent IFNg exposure inhibits HSC self-renewal,
eventually leading to bone marrow failure. Whether HSCs or their progeny, the multipotent progenitors (MPPs),
are equally responsive to IFNg is unknown. Furthermore, a lack of molecular understanding of signaling
pathways induced by IFNg to promote HSPC differentiation poses a barrier to utilizing proimmune functions of
IFNg while preventing deleterious effects. In preliminary work we identify genes induced in HSCs upon IFNg
stimulation, and we show by gain- and loss-of-function studies that an exemplary gene can critically regulate
HSPC differentiation. Thus we hypothesize that IFNg-induced transcriptional changes can be used to activate
quiescent HSCs to produce more neutrophils, resulting in improved recovery from infection. The rationale is
that regulated induction of specific IFNg targets in HSCs may enhance short-term myelopoiesis without
disrupting long-term bone marrow function. Three aims are designed to characterize the kinetics, mechanism,
and outcome of IFNg-dependent HSPC differentiation. In Aim 1, we will measure the contribution of HSCs
versus MPPs to circulating granulocytes after IFNg stimulation using lineage-tracing, thereby revealing which
of these HSPC subtypes is most potent as a source of neutrophils. In Aim 2, we will evaluate IFNg-inducible
factors for their role in HSPC differentiation using loss of function, xenotransplant, and functional biochemical
studies. Finally, in Aim 3, we will test the utility of IFNg-induced HSPC myeloid differentiation in pathogen
clearance using a mouse model of Group A Streptococcal myositis. Studies in Aim 3 will be informed by, but
not dependent on, results of Aims 1 and 2. These studies will provide critical mechanistic data needed to
design novel stem cell-based therapies for neutropenic fever and may reveal new insights into bone marrow
failure syndromes that result from excessive inflammation.

## Key facts

- **NIH application ID:** 9948728
- **Project number:** 5R01HL134880-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Katherine Yudeh King
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,609
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948728

## Citation

> US National Institutes of Health, RePORTER application 9948728, Inflammatory Regulation of Hematopoietic Stem and Progenitor Cells to Enhance Innate Immunity (5R01HL134880-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948728. Licensed CC0.

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