Proinflammatory Milieu Disrupts Homeostatic Microglia-Vascular Interactions to Promote Germinal Matrix Hemorrhage

Download This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL Proinflammatory Milieu Disrupts Homeostatic Microglia-Vascular Interactions to Promote Germinal Matrix Hemorrhage Cell 52 Pages Posted: 4 Nov 2022 Publication Status: Under Review See all articles by Jiapei ChenJiapei ChenUniversity of California, San Francisco (UCSF) - Department of PathologyElizabeth Erin CrouchUniversity of California, San Francisco (UCSF) - Biomedical Sciences Graduate ProgramShamari WallerUniversity of California, San Francisco (UCSF) - Department of PathologyAvani KelekarUniversity of California, San Francisco (UCSF) - Department of PathologyGugene KangUniversity of California, San Francisco (UCSF) - Department of Neurological SurgeryLoukas N. DiafosUniversity of California, San Francisco (UCSF), School of Medicine, Division of Hematology/Oncology, Department of PediatricsKaylee Wedderburn-PughUniversity of California, San Francisco (UCSF) - Biomedical Sciences Graduate ProgramBarbara Di MarcoHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - Department of Clinical NeurobiologyWenlong XiaUniversity of California, San Francisco (UCSF) - Department of NeurologyEdward J. ValenzuelaUniversity of California, San Francisco (UCSF), School of Medicine, Division of Hematology/Oncology, Department of PediatricsClaudia Z. HanUniversity of California, San Diego (UCSD) - Department of Cellular & Molecular MedicineNicole G. CoufalRady Children's HospitalChristopher K. GlassUniversity of California, San Diego (UCSD) - Department of Cellular & Molecular MedicineStephen PJ FancyUniversity of California, San Francisco (UCSF) - Biomedical Sciences Graduate ProgramJulieta AlfonsoHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - Department of Clinical NeurobiologyMichael C. OldhamUniversity of California, San Francisco (UCSF) - Biomedical Sciences Graduate ProgramEric HuangUniversity of California, San Francisco (UCSF) - The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research More... Abstract Ganglionic eminences (GEs), also known as germinal matrix, are vulnerable to develop hemorrhage in prenatal human brain. However, the mechanism for germinal matrix hemorrhage remains unknown. Here, we show that immune cells age-dependently regulate vascular morphogenesis in GEs, but not in cortical plates. Using single-cell transcriptomics, we show that distinct subsets of CD45+ immune cells employ diverse signaling mechanisms to promote the formation of vascular network in GEs. Similar transcriptomic profiling of CD45+ cells from cases with germinal matrix hemorrhage show that activated neutrophils and monocytes utilize bactericidal factors and CXCL16 signaling, respectively, to disrupt nascent vasculature in the germinal matrix. This proinflammatory milieu alters S1PR1 signaling in the endothelial cells, which exacerbates the migration of immune cells across primitive blood-brain barriers. These results underscore the critical roles of brain's innate immune cells in region-specific angiogenesis and how perturbations to this process contributes to germinal matrix hemorrhage in preterm infants.Funding Information: This work has been supported by the AHA Predoctoral Fellowship 19PRE3480616 and UCSF Discovery Fellowship to J.C., the Eli and Edythe Broad Regeneration Medicine and Stem Cell Fellowship, Pediatric Scientist Development Program (5K12HD000850-34), UCSF Physician Scientist Scholars Program (PSSP), American Heart Association Career Development Grant 857876, CIRM Alpha Stem Cell Clinic Fellowship, and NIH K08 NS116161 to E.E.C., NIH K99/R00 MH129983 to C.Z.H., NIH R01 NS124637 to N.G.C., NIH grants P01 NS083513 to S.P.J.F. and E.J.H. and U01 MH105989 to E.J.H..Conflict of Interests: Authors declare that they have no competing interests.Ethical Approval: The autopsy consent and all protocols for human prenatal brain tissue procurement were approved by the Human Gamete, Embryo and Stem Cell Research Committee (Institutional Review Board GESCR# 10-02693) at the University of California, San Francisco (UCSF) and by the UC San Diego Institutional Review Board (IRB 171379). All experiments were conducted in accordance with the University of California San Francisco Institutional Animal Care and Use Committee guidelines (IACUC Protocol #AN169548). Keywords: Angiogenesis, homeostatic microglia, monocytes, HLA+ myeloid cells, neutrophils, Inflammation, CXCL16, S1PR1, transendothelial migration, germinal matrix, hemorrhage Suggested Citation: Suggested Citation Chen, Jiapei and Crouch, Elizabeth Erin and Waller, Shamari and Kelekar, Avani and Kang, Gugene and Diafos, Loukas N. and Wedderburn-Pugh, Kaylee and Di Marco, Barbara and Xia, Wenlong and Valenzuela, Edward J. and Han, Claudia Z. and Coufal, Nicole G. and Glass, Christopher K. and Fancy, Stephen PJ and Alfonso, Julieta and Oldham, Michael C. and Huang, Eric, Proinflammatory Milieu Disrupts Homeostatic Microglia-Vascular Interactions to Promote Germinal Matrix Hemorrhage. Available at SSRN: https://ssrn.com/abstract=4260494 This version of the paper has not been formally peer reviewed. Jiapei Chen (Contact Author) University of California, San Francisco (UCSF) - Department of Pathology ( email ) Elizabeth Erin Crouch University of California, San Francisco (UCSF) - Biomedical Sciences Graduate Program ( email ) Shamari Waller University of California, San Francisco (UCSF) - Department of Pathology ( email ) Avani Kelekar University of California, San Francisco (UCSF) - Department of Pathology ( email ) Gugene Kang University of California, San Francisco (UCSF) - Department of Neurological Surgery ( email ) Loukas N. Diafos University of California, San Francisco (UCSF), School of Medicine, Division of Hematology/Oncology, Department of Pediatrics ( email ) Kaylee Wedderburn-Pugh University of California, San Francisco (UCSF) - Biomedical Sciences Graduate Program ( email ) Barbara Di Marco Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - Department of Clinical Neurobiology ( email ) Wenlong Xia University of California, San Francisco (UCSF) - Department of Neurology ( email ) Edward J. Valenzuela University of California, San Francisco (UCSF), School of Medicine, Division of Hematology/Oncology, Department of Pediatrics ( email ) Claudia Z. Han University of California, San Diego (UCSD) - Department of Cellular & Molecular Medicine ( email ) Nicole G. Coufal Rady Children's Hospital ( email ) Christopher K. Glass University of California, San Diego (UCSD) - Department of Cellular & Molecular Medicine ( email ) Stephen PJ Fancy University of California, San Francisco (UCSF) - Biomedical Sciences Graduate Program ( email ) Julieta Alfonso Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH) - Department of Clinical Neurobiology ( email ) Michael C. Oldham University of California, San Francisco (UCSF) - Biomedical Sciences Graduate Program ( email ) Eric Huang University of California, San Francisco (UCSF) - The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research ( email ) San Francisco, CAUnited States Download This Paper Open PDF in Browser Please enable JavaScript to view the comments powered by Disqus. 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