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Genome-wide gene expression profiling post PCCB knockdown in human forebrain organoids

ABSTRACT: We established PCCB knockdown human induced pluripotent stem cell (hiPSC) line using CRISPR interference (CRISPRi). The established PCCB knockdown and control hiPSCs were then used to generate human forebrain organoids (hFOs). On day 60 of organoid culture, PCCB knockdown and control hFOs were randomly selected for RNA-sequencing (RNA-seq). We found that differentially expressed genes (DEGs) affected by PCCB knockdown were enriched with GABAergic synapse, synaptic vesicle cycle, neurotransmitter transport, forebrain development, axon development, synaptic organization, and calcium signaling pathways. The DEGs were also significantly overlapped with schizophrenia (SCZ)-associated genes, including genes dysregulated in brains or organoids derived from SCZ patients, and genes reported in SCZ GWAS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226233 | GEO | 2023/05/02

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) derive from the hemogenic endothelium of the dorsal aorta, which develops in spatial and functional proximity to the heart anlagen in the human embryo. Despite the biomedical importance of HSCs, their in vitro induction and niche-like stabilization in a proper developmental context is challenging and poorly established. The underlying reasons include the poorly understood signals controlling HSC formation and the lack of unequivocal markers specifying their stages of differentiation and maturation. Our recently established human pluripotent stem cell (hPSC)-derived heart-forming organoids (HFOs) represent complex, well-patterned multi-tissue structures recapitulating key aspects of heart, foregut and vasculature development. Modulating HFO development by the stage-dependent supplementation of hemato-endothelial factors, we here report the generation of blood-generating-HFOs (BG-HFOs). While maintaining their well-patterned heart anlagen, BG-HFOs comprise a dense, mesenchyme-embedded endothelial layer giving rise to hematopoietic cells thereby resembling – in vitro - aspects of the intra-embryonic region giving rise to definitive hematopoiesis in vivo. Single cell-RNA sequencing of BG-HFOs revealed a gene expression signature of hematopoietic progenitor cells (HPCs) as well as patterns resembling hematopoietic derivatives such as erythroid, megakaryocytic and myeloid cells. Notably, BG-HFO-derived CD34pos CD43pos and CD34neg CD43pos cells display erythroid and myeloid potential in colony forming unit (CFU) assays, while CD34pos CD43neg HPCs retain lymphoid potential, observed via generation of T-cell progenitors in artificial thymic organoid (ATO)-based assays. This suggests presence of different multipotent HPCs in BG-HFOs and a potential transient downregulation of CD43 in lymphoid-restricted HPCs. Together, BG-HFOs represent the first human model of cardiac, endothelial and multipotent-hematopoietic cell co-development. The study promotes research on the multi-tissue interactions of hematopoiesis in vitro, overcoming limitations of such studies in the human embryo.

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Genome-wide gene expression profiling post PCCB knockdown in human forebrain organoids

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