Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain
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<sup>+</sup> cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45<sup>+</sup> 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.
Authors
- Jiapei Chen (ORCID: https://orcid.org/0000-0002-8205-8593)
- Michael C. Oldham (ORCID: https://orcid.org/0000-0001-7633-6932)
- Barbara Di Marco (ORCID: https://orcid.org/0000-0003-1751-7455)
- Edward J. Valenzuela (ORCID: https://orcid.org/0000-0003-3234-5460)
- José Manuel García‐Verdugo (ORCID: https://orcid.org/0000-0001-9872-6499)
- Arnold R. Kriegstein (ORCID: https://orcid.org/0000-0001-5742-2990)
- Pin-Yeh Lin
- Matthew L. Kutys (ORCID: https://orcid.org/0000-0002-0752-649X)
- Saba Shaikh (ORCID: https://orcid.org/0009-0000-9272-3713)
- Janeth O. Birrueta (ORCID: https://orcid.org/0000-0003-4559-5805)
- Gugene Kang (ORCID: https://orcid.org/0000-0002-2960-7434)
- Elizabeth E. Crouch (ORCID: https://orcid.org/0000-0002-4110-9892)
- Jennifer Ja-Yoon Choi
- Maria K. Lehtinen (ORCID: https://orcid.org/0000-0002-7243-2967)
- Stephen P.J. Fancy (ORCID: https://orcid.org/0000-0002-2818-8258)
- Eric J. Huang (ORCID: https://orcid.org/0000-0002-5381-3801)
- Christopher K. Glass (ORCID: https://orcid.org/0000-0003-4344-3592)
- Kaylee Wedderburn-Pugh (ORCID: https://orcid.org/0000-0002-5501-0519)
- Jessica Tsui (ORCID: https://orcid.org/0000-0002-1336-6760)
- Julieta Alfonso (ORCID: https://orcid.org/0000-0002-5063-3653)
- Nicole G. Coufal (ORCID: https://orcid.org/0000-0001-6547-1733)
- Alexis J. Combes (ORCID: https://orcid.org/0000-0002-9110-6542)
- Loukas N. Diafos
- Kyle A. Jacobs (ORCID: https://orcid.org/0000-0002-4411-7855)
- Claudia Z. Han (ORCID: https://orcid.org/0000-0002-2285-5582)
- Miriam E. Zawadzki
- Lakyn Mayo (ORCID: https://orcid.org/0000-0002-6642-2332)
- Avani Kelekar
- Wenlong Xia
- Susana González-Granero (ORCID: https://orcid.org/0000-0003-1531-550X)
- Shamari Waller
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Universitat de València (ES)
- German Cancer Research Center (DE)
- University of California, San Francisco (US)
- Heidelberg University (DE)
- Instituto de Salud Carlos III (ES)
- University Hospital Heidelberg (DE)
- University of California San Diego (US)
- San Francisco VA Health Care System (US)
- Broad Center (US)
- Neurological Surgery (US)
- University of San Francisco (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41593-024-01769-2
- Citations
- 15
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.71
Funders
- National Science Foundation
- American Heart Association
- National Institutes of Health
- University of California, San Francisco
- National Institute on Aging
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Institute of Neurological Disorders and Stroke