# Role and Regulation of Neural Stem Cells in Remyelination

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $424,733

## Abstract

Project Summary
Both oligodendrocyte progenitors (OPCs) and neural stem cells (NSCs) in the subventricular zone (SVZ)
are known sources of remyelinating oligodendrocytes. Their precise contribution to remyelination and
what limits their effectiveness in repair are active areas of research with important therapeutic
implications. We have found that Sonic hedgehog (Shh)-responsive adult NSCs are a significant source
of remyelinating cells. These NSCs, which are enriched in the ventral SVZ, normally give rise to
parenchymal astrocytes and interneurons. They only enter white matter tracts upon demyelination,
including to the the demyelinated corpus callosum (CC), where they are robustly recruited and
differentiate preferentially into oligodendroglia. Unexpectedly, their recruitment to such lesions and their
differentiation into remyelinating oligodendrocytes is significantly enhanced by genetic ablation or
pharmacological inhibition of the Shh-dependent transcription factor Gli1. Further, pharmacological
inhibition of Gli1 enhances remyelination in the adult and improves functional recovery from
inflammatory demyelination. Important questions include whether their contribution to remyelination is
impacted by competition with parenchymal OPCs during repair, what recruits these cells to demyelinated
lesions, and how Gli1 limits NSC repair. In Aim 1, we examine whether NSCs expand their contribution
to repair if OPC remyelination is blocked to assess whether NSC and OPCs compete to remyelinate the
same lesion sites. In Aim 2, we assess the role of microglia (MG) and astrocytes, which are both
activated in lesion sites, in the expansion and recruitment of NSCs. Our preliminary studies suggest MG
are essential for NSC expansion and recruitment but do not indicate if this is a direct effect or is
secondary to activation of astroglia. In Aim 3, we will investigate a novel NSC phenotype revealed by
RNAseq that is only upregulated with demyelination and is Gli1- dependent. This phenotype includes a
number of inflammation-related mediators and the C1q complex. We will characterize this altered NSC
phenotype further, examine its potential role in regulating the number and phenotype of MG in the SVZ,
and assess its potential impact on NSC clearance and remyelination. These studies will provide
important, new insights into the signals (cells and molecules) that regulate the contribution of stem cells
to repair and may thereby guide therapeutic efforts to promote remyelination.

## Key facts

- **NIH application ID:** 10155591
- **Project number:** 5R01NS100867-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** JAMES SALZER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $424,733
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155591

## Citation

> US National Institutes of Health, RePORTER application 10155591, Role and Regulation of Neural Stem Cells in Remyelination (5R01NS100867-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155591. Licensed CC0.

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