# Regulation of hematopoietic stem cell niche aging by the sympathetic nervous system

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $566,022

## Abstract

PROJECT SUMMARY:
Hematopoietic aging is associated with a decline in the regenerative capacity of hematopoietic stem cells
(HSCs), leading to the development of blood disorders and loss of immune function. We have previously
demonstrated that aging leads to sympathetic neuropathy of the BM and that premature loss of nerves or
adrenergic receptor β3 (Adrβ3) accelerated the appearance of intrinsic aging-like phenotypes in HSC. In
contrast, supplementation of β3-adrenergic agonists to boost signaling in aged mice rejuvenated niche and
HSC function. However, mechanisms downstream of the SNS that drive the phenotypic features of aging niche
and HSCs remain unclear. In the healthy BM, perivascular stromal cells containing all mesenchymal stem cell
(MSC) activity are regulated by oscillatory signals from the SNS that control the mobilization of hematopoietic
stem and progenitor cells into peripheral blood. BM MSCs comprise two distinct subpopulations: peri-arteriolar
MSCs (periMSC), directly innervated by the SNS, and peri-sinusoidal reticular MSCs (reticMSCs) denuded from
innervation. Although reticMSCs are found away from sympathetic nerves, they are targeted by the SNS to
mediate HSC maintenance and trafficking. Preliminary data supporting this application provide evidence that
aged reticMSCs exhibit significant alterations in redox signaling and glucose metabolism pathways that are
controlled by the SNS. Furthermore, we have identified a potential mechanism of neural signal transmission in
the niche that depends on connexin gap junctions and peri-arteriolar NADPH Oxidase (NOX). We show that
the generation of reactive oxygen species (ROS) by the NOX complex in MSCs depends on signals from the
SNS and that targeting NOX, specifically in periMSCs, induced aging-like phenotypes in reticMSCs and HSCs.
Based on our findings, we hypothesize that NOX-derived ROS transduce β-adrenergic signals via connexin gap
junctions and that loss of ROS transmission deregulates reticMSC homeostasis, leading to expansion of
metabolically dysfunctional subsets that are unable to maintain HSCs. This hypothesis will be tested in two aims.
In Specific Aim 1, we propose to define the mechanism of neural signal transduction by using a novel MSC
culture system and assess the role of connexins and ROS in stromal cell-to-cell communication using
pharmacologic and genetic means. In Specific Aim 2, we will investigate how SNS-enabled stromal ROS
homeostasis and mitochondrial metabolism alter MSC and niche function to regulate HSC aging. Our proposed
studies will identify new mechanisms of HSC aging and help devise therapeutic rejuvenation strategies to
improve or prevent the course of age-associated hematopoietic diseases.

## Key facts

- **NIH application ID:** 10941134
- **Project number:** 1R01HL174801-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Maria Marianovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $566,022
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941134

## Citation

> US National Institutes of Health, RePORTER application 10941134, Regulation of hematopoietic stem cell niche aging by the sympathetic nervous system (1R01HL174801-01). Retrieved via AI Analytics 2026-06-22 from https://api.ai-analytics.org/grant/nih/10941134. Licensed CC0.

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