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Published on: January 26, 2024
Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain
Jiapei Chen1,2, Elizabeth E Crouch2,3,4, Miriam E Zawadzki5,6,7
1Department of Pathology and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Abstract:
Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain's innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants.
Insights
Microglia play a key role in brain blood vessel development. In preterm infants with germinal matrix hemorrhage (GMH), activated immune cells disrupt these vessels, causing brain bleeds.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Germinal matrix hemorrhage (GMH) is a severe neurodevelopmental issue in preterm infants.
- The precise cause of blood vessel fragility in the germinal matrix remains unclear.
Purpose of the Study:
- To investigate the role of brain immune cells, specifically microglia, in the development of germinal matrix hemorrhage (GMH).
- To identify the mechanisms by which immune cells contribute to vascular fragility in the preterm brain.
Main Methods:
- Utilized mouse models with targeted ablation of microglia.
- Conducted single-cell transcriptomics and flow cytometry on immune cells (CD45+) from preterm infants with and without GMH.
- Analyzed the interaction between microglia and nascent vasculature in prenatal brain tissue.
Main Results:
- Microglia interact with developing blood vessels in an age-dependent manner.
- Depletion of microglia in mice impaired angiogenesis in the ganglionic eminences.
- Immune cells (CD45+) from infants with GMH showed activated neutrophils and monocytes producing inflammatory factors that disrupt vascular integrity.
- These factors promote hemorrhage in the ganglionic eminences.
Conclusions:
- Brain's innate immune cells are crucial for region-specific blood vessel formation (angiogenesis).
- Aberrant activation of these immune cells in preterm infants contributes to the pathogenesis of GMH.
- Understanding these mechanisms may lead to novel therapeutic strategies for preventing GMH.
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