Systematic Identification of Cell-Cell Communication Networks in the Developing Brain.

Bilal N. Sheikh,Lutz Hein,Katarzyna Sikora,Nadim Aizarani,Herbert Holz,Asifa Akhtar,Tsz Hong Tsang,Dominic Grün,Olga Bondareva,Sagar Sagar,Sukanya Guhathakurta

doi:10.1016/j.isci.2019.10.026

Bilal N. Sheikh, Lutz Hein + Show 9 more

Open Access

https://doi.org/10.1016/j.isci.2019.10.026

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Abstract

SummarySince the generation of cell-type specific knockout models, the importance of inter-cellular communication between neural, vascular, and microglial cells during neural development has been increasingly appreciated. However, the extent of communication between these major cell populations remains to be systematically mapped. Here, we describe EMBRACE (embryonic brain cell extraction using FACS), a method to simultaneously isolate neural, mural, endothelial, and microglial cells to more than 94% purity in ∼4 h. Utilizing EMBRACE we isolate, transcriptionally analyze, and build a cell-cell communication map of the developing mouse brain. We identify 1,710 unique ligand-receptor interactions between neural, endothelial, mural, and microglial cells in silico and experimentally confirm the APOE-LDLR, APOE-LRP1, VTN-KDR, and LAMA4-ITGB1 interactions in the E14.5 brain. We provide our data via the searchable “Brain interactome explorer”, available at https://mpi-ie.shinyapps.io/braininteractomeexplorer/. Together, this study provides a comprehensive map that reveals the richness of communication within the developing brain.

Highlights

Embryonic development is a highly reproducible process that requires extensive communication between cells
The presence and functionality of vascular cells and microglia is critical for proper neural development, and dysregulation of these cells results in severe neural disorders (Daneman et al, 2010b; Matcovitch-Natan et al, 2016; Mathys et al, 2017; Sengillo et al, 2013; Vasudevan et al, 2008)
Sorting Strategy for the Isolation of Neural, Microglial, and Vascular Cells In the current study, we set out to establish a protocol for the simultaneous isolation of neural, mural, endothelial, and microglial cells and systematically map interactions between these four cell types

Summary

Introduction

Embryonic development is a highly reproducible process that requires extensive communication between cells. In addition to the neural lineage, microglia, the resident immune cells of the central nervous system, as well as vascular endothelial cells and pericytes are present in the developing brain (Alliot et al, 1999; Daneman et al, 2010b; Vasudevan et al, 2008). VEGF-A released by neural progenitor cells is detected by endothelial cells and is critical for proper angiogenesis and vascularization of the developing brain (Haigh et al, 2003). Despite the accumulation of evidence that interactions between neural cells, microglia, and vascular cells are critical for proper brain development, the identity of the molecules that mediate these inter-cellular interactions remains to be systematically mapped

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