# Neuroinflammation and vascular development in GMH

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $580,701

## Abstract

SUMMARY
 Preterm infants born between 21 to 30 gestational weeks (GW) have 20-40% chance of developing germinal
matrix hemorrhage (GMH), which is a leading cause of neonatal mortality and neurodevelopmental disorders,
such as cerebral palsy. Despite decades of research, however, there has been no significant improvement in
the prevalence of preterm birth and the mechanism leading to GMH remains unclear. To understand the cause(s)
for GMH, we have shown that, during the second trimester, germinal matrix contains enriched populations of
Nestin+ radial glia and DCX+ neuroblasts that are fated to become GABAergic interneurons. Furthermore, DCX+
neuroblasts in the germinal matrix are organized as distinct clusters, called DCX-Enriched Nests or DENs, where
they expand and migrate to the cerebral cortex and other deep nuclei before becoming mature GABAergic
interneurons and integrating into the local neural circuits. To investigate why blood vessels in the germinal matrix
are particularly vulnerable to develop GMH, we combined histological and ultrastructural analyses, fluorescence-
activated cell sorting (FACS), and single-cell transcriptomics to characterize the properties of nascent blood
vessels in the prenatal human brain from 15 to 25 GW. These studies lead to three main conclusions. First,
during the second trimester the vascular network in the germinal matrix is much more complex than other brain
regions. These nascent blood vessels are tiled by an ensemble of endothelial cells and mural cells, which follow
distinct developmental trajectories and use diverse signaling mechanisms to facilitate cell-cell communication
and maturation. Second, endothelial cells from younger brain (15-18 GW) exhibit stage-specific transcriptomic
and bioenergetic features that are different from those from 20-23 GW. In addition, microglia-vasculature
interactions stage-dependently promote angiogenesis in the germinal matrix, but not in the cortical plate. Finally,
transcriptomic profiling of CD45+ cells in GMH cases showed that proinflammatory neutrophils and monocytes
utilize antibacterial factors and CXCL16-S1PR1 signaling, respectively, to disrupt nascent vasculature in the
germinal matrix. Collectively, our results support the overarching hypothesis that proinflammatory
neutrophils and monocytes produce cytotoxic factors to disrupt angiogenesis and neurogenesis in the
germinal matrix of preterm infants with GMH. To test this hypothesis, we propose to (1) characterize the
cytotoxic properties of neutrophil-produced antibacterial factors in disrupting angiogenesis, (2) determine the
impacts of CXCL16-S1PR1-mediated signaling in angiogenesis in the germinal matrix, and (3) examine the
impacts of GMH on the neurogenesis and migration of GABAergic interneurons. Results from this project will
provide important insights into disease mechanism of, and therapeutic targets for, GMH.

## Key facts

- **NIH application ID:** 10685146
- **Project number:** 1R01NS132595-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $580,701
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685146

## Citation

> US National Institutes of Health, RePORTER application 10685146, Neuroinflammation and vascular development in GMH (1R01NS132595-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10685146. Licensed CC0.

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