Complement C4 Is Reduced in iPSC-Derived Astrocytes of Autism Spectrum Disorder Subjects.

Fernanda Mansur,André Luiz Teles E Silva,Juliana Magdalon,Maria Rita Passos-Bueno,Janaina Sena De Souza,Andréa Laurato Sertié,Ana Karolyne Santos Gomes,Karina Griesi-Oliveira

doi:10.3390/ijms22147579

Abstract

In recent years, accumulating evidence has shown that the innate immune complement system is involved in several aspects of normal brain development and in neurodevelopmental disorders, including autism spectrum disorder (ASD). Although abnormal expression of complement components was observed in post-mortem brain samples from individuals with ASD, little is known about the expression patterns of complement molecules in distinct cell types in the developing autistic brain. In the present study, we characterized the mRNA and protein expression profiles of a wide range of complement system components, receptors and regulators in induced pluripotent stem cell (iPSC)-derived neural progenitor cells, neurons and astrocytes of individuals with ASD and neurotypical controls, which constitute in vitro cellular models that recapitulate certain features of both human brain development and ASD pathophysiology. We observed that all the analyzed cell lines constitutively express several key complement molecules. Interestingly, using different quantification strategies, we found that complement C4 mRNA and protein are expressed in significantly lower levels by astrocytes derived from ASD individuals compared to control astrocytes. As astrocytes participate in synapse elimination, and diminished C4 levels have been linked to defective synaptic pruning, our findings may contribute to an increased understanding of the atypically enhanced brain connectivity in ASD.

Highlights

Introduction published maps and institutional affilThe complement system, which plays crucial roles in the innate defense against pathogens and damaged cells [1], has been increasingly implicated in brain development and plasticity [2,3]
Human induced pluripotent stem cell-derived brain cells have been successfully used to model autism spectrum disorder (ASD) [23,24,25,26,27] and we have recently shown that the transcriptome profiles from iPSC-derived neural progenitor cells (NPCs) and neurons best reflects neuronal tissue at early (4–10 post-conception weeks) and middle (16–24 post-conception weeks) stages of prenatal brain development, respectively [27]
Generation of iPSC-Derived Neural Progenitor Cells, Neurons and Astrocytes from ASD and Control Subjects iPSCs from individuals with ASD (n = 7) and control subjects (n = 4) were differentiated into NPCs, post-mitotic neurons and astrocytes, and the expression of lineage-specific markers was measured by western blotting and qualitatively confirmed by immunocytochemistry

Summary

Introduction

The complement system, which plays crucial roles in the innate defense against pathogens and damaged cells [1], has been increasingly implicated in brain development and plasticity [2,3]. All major cell types in the brain have been shown to constitutively express at least some components, receptors and regulators of the three pathways of complement activation (classical, lectin and alternative), which contribute to some key cellular processes in the developing brain, including neurogenesis [4], neuronal migration [5] and synapse pruning and remodeling [6,7,8,9]. Inappropriate expression or activation of the complement system might alter the establishment of precise neural networks in the brain during development, resulting in cognitive dysfunction. A growing number of studies has associated dysregulation of specific components of the complement system with neurodevelopmental disorders [10], such as schizophrenia [8] and autism spectrum disorder (ASD) [11,12]. iations.

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