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Pro-inflammatory cytokine stimulation of human cortical spheroids containing neuroectoderm-derived and mesoderm-derived cell types

ABSTRACT: Pro-inflammatory cytokine stimulation of human cortical spheroids containing neuroectoderm-derived and mesoderm-derived cell types

PROVIDER: PRJNA826732 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18750309.fastq.gz	Fastqsanger.gz
	SRR18750310.fastq.gz	Fastqsanger.gz
	SRR18750311.fastq.gz	Fastqsanger.gz
	SRR18750312.fastq.gz	Fastqsanger.gz
	SRR18750313.fastq.gz	Fastqsanger.gz

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Pro-inflammatory cytokine stimulation of human cortical spheroids containing neuroectoderm-derived and mesoderm-derived cell types

Project description:Three-dimensional (3D) human brain spheroids are instrumental to study central nervous system (CNS) development and (dys)functioning. Yet, in current brain spheroid models the limited variety of cell types hampers an integrated exploration of CNS (disease) mechanisms. In this study, we developed a five-months culture protocol that reproducibly generates H9 embryonic stem cell-derived human cortical spheroids (hCSs) comprising not only neuroectoderm-derived neural progenitor populations, mature excitatory and inhibitory neurons, astrocytes and oligodendrocyte (precursor) cells, but also mesoderm-derived microglia and endothelial cell populations. We then set out to explore the effects of stimulating our hCSs for three time periods with the cytokines TNFα and IL-1β. We use transcriptome-wide RNA-sequencing (RNA-seq) analysis to show that the major process induced by TNFα as well as by IL-1β is neuroinflammation. Central in this process are endothelial cells, microglia and astrocytes, and activation of the NFκB and STAT pathways. In addition to this equiva-lent impact of TNFα and IL-1β, we find that each of the two cytokines has specific and stimulation-time-dependent effects on hCS gene expression, and that IL-1β exhibits a faster self-inhibitory feedback response to dampen neuroinflammation than TNFα. Thus, our protocol provides an inducible 3D human brain cell model containing a wide variety of innately developing neuroectoderm- as well as mesoderm-derived cell types, furnishing a versatile platform for comprehensive examination of intercellular CNS communication and neurological disease mechanisms.

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