# Mechanisms regulating the aging of HSC niches

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $375,750

## Abstract

PROJECT SUMMARY:
Mammalian aging is associated with reduced tissue regeneration due to declining function of tissue-specific
stem cells. In the blood system, hematopoietic stem cell (HSC) aging is accompanied by an expansion of
myeloid-biased HSCs with reduced self-renewal functions. Aging of HSCs and their niches likely contributes to
aged-related hematologic malignancies such a myelodysplastic syndromes or acute myelogenous leukemia.
Whether the aging microenvironment drives the phenotypic features of aging HSCs, however, remains unclear.
In the healthy bone marrow of young mice, our prior studies show that niches cells containing mesenchymal
stem cell (MSC) activity, marked by Nestin expression, are innervated and regulated by the sympathetic
nervous system (SNS). Preliminary data supporting this grant application have revealed marked alterations in
the vasculature of aged bone marrow, associated with loss of SNS innervation, and increased Nestin+ cell
numbers. In addition, we find that the generation of reactive oxygen species (ROS) in endothelial and
perivascular cells oscillates in a circadian manner, and that these oscillations are impaired in aged bone
marrow. Aged bone marrow endothelial cells also exhibit significant alterations in glucose metabolism, that are
regulated by SNS-derived signals. Based on these preliminary data, we propose to explore the hypothesis that
the loss of SNS nerve signals contributes to the hematopoietic aging phenotype via regulation of the vascular-
associated niche cells. This hypothesis will be tested in three aims wherein: Specific Aim 1 will investigate the
function of β-adrenergic signals in the aging HSC niche using pharmacological and genetic approaches to
modulate the sympathetic tone. In Specific Aim 2, we will investigate how SNS-enabled circadian rhythms and
ROS homeostasis alter MSCs and niche function to regulate niche structure and HSC aging phenotypes.
Specific Aim 3 will investigate the role of SNS innervation in age-related alterations of vascular metabolism in
the HSC niche. The proposed studies will shed new light on the contributions of the aging niche on HSC
function, and will help to devise new therapeutic strategies to prevent or improve the course of age-associated
hematopoietic diseases.#

## Key facts

- **NIH application ID:** 9850586
- **Project number:** 5R01DK112976-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Paul S Frenette
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,750
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850586

## Citation

> US National Institutes of Health, RePORTER application 9850586, Mechanisms regulating the aging of HSC niches (5R01DK112976-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850586. Licensed CC0.

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