Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain

Elizabeth E Crouch; Aparna Bhaduri; Madeline G Andrews; Arantxa Cebrian-Silla; Loukas N Diafos; Janeth Ochoa Birrueta; Kaylee Wedderburn-Pugh; Edward J Valenzuela; Neal K Bennett; Ugomma C Eze; Carmen Sandoval-Espinosa; Jiapei Chen; Cristina Mora; Jayden M Ross; Clare E Howard; Susana Gonzalez-Granero; Jaime Ferrer Lozano; Maximo Vento; Maximilian Haeussler; Mercedes F Paredes; Ken Nakamura; Jose Manuel Garcia-Verdugo; Arturo Alvarez-Buylla; Arnold R Kriegstein; Eric J Huang

doi:10.1016/j.cell.2022.09.004

Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain

Cell. 2022 Sep 29;185(20):3753-3769.e18. doi: 10.1016/j.cell.2022.09.004.

Authors

Elizabeth E Crouch¹, Aparna Bhaduri², Madeline G Andrews³, Arantxa Cebrian-Silla⁴, Loukas N Diafos⁵, Janeth Ochoa Birrueta⁵, Kaylee Wedderburn-Pugh⁶, Edward J Valenzuela⁵, Neal K Bennett⁷, Ugomma C Eze⁸, Carmen Sandoval-Espinosa⁹, Jiapei Chen¹⁰, Cristina Mora¹¹, Jayden M Ross³, Clare E Howard¹², Susana Gonzalez-Granero¹³, Jaime Ferrer Lozano¹⁴, Maximo Vento¹⁵, Maximilian Haeussler¹⁶, Mercedes F Paredes¹⁷, Ken Nakamura¹⁸, Jose Manuel Garcia-Verdugo¹³, Arturo Alvarez-Buylla¹⁹, Arnold R Kriegstein¹⁷, Eric J Huang²⁰

Affiliations

¹ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental & Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
⁸ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental & Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹¹ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
¹³ Laboratorio de Neurobiología Comparada, Instituto Cavanilles de Biodiversidad y 21 Biología Evolutiva, Universitat de València - Centro de Investigación Biomédica en Red 22 sobre Enfermedades Neurodegenerativas, Valencia, Spain.
¹⁴ Department of Pathology, Hospital Universitari i Politecnic La Fe, Valencia, Spain.
¹⁵ Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain; Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁶ Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95060, USA.
¹⁷ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental & Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁸ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
¹⁹ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental & Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
²⁰ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Science Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental & Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Pathology Service 113B, San Francisco Veterans Affairs Healthcare System, San Francisco, CA 94121, USA. Electronic address: [email protected].

Abstract

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.

Keywords: angiogenesis; arterial endothelial cells; blood brain barrier; cortical organoids; endothelial cells; human prenatal brain development; mural cells; pericytes; smooth muscle cells; tip cells; venous and capillary endothelial cells; ventricular zone.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Brain
Collagen
Endothelial Cells*
Humans
Laminin
Midkine
Neovascularization, Pathologic / pathology
Neovascularization, Physiologic* / physiology
Pericytes

Substances

Laminin
Midkine
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding