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Multilineage communication regulates human liver bud self-organization from pluripotency II

ABSTRACT: Multilineage communication regulates human liver bud self-organization from pluripotency II

OTHER RELATED OMICS DATASETS IN: GSE96981

PROVIDER: PRJNA380268 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5373790_1.fastq.gz	Fastqsanger.gz
	SRR5373790_2.fastq.gz	Fastqsanger.gz
	SRR5373800_1.fastq.gz	Fastqsanger.gz
	SRR5373800_2.fastq.gz	Fastqsanger.gz
	SRR5373810_1.fastq.gz	Fastqsanger.gz

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Multilineage communication regulates human liver bud self-organization from pluripotency I

Project description:Conventional 2-D differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. 3-D organoids generate complex organ-like tissues, however it is unclear how heterotypic interactions impact lineage identity. Here we use single-cell RNA-seq to reconstruct hepatocyte-like lineage progression from pluripotency in 2-D culture. We then derive 3-D liver bud (LB) organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during LB self-organization. We find that LB hepatoblasts differentiate towards hepatocyte fate, and in addition express epithelial migration signatures characteristic of organ budding. We identify hypoxia and inflammation signatures in endothelial and mesenchymal cells, which we suggest induce LB vasculogenesis. We use network analysis to predict autocrine and paracrine signaling in LBs, and show that VEGF crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals inter-lineage communication that is required for self-organization, and illuminates previously inaccessible aspects of human organ development and regeneration.

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Multilineage communication regulates human liver bud self-organization from pluripotency II

Project description:Conventional 2-D differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. 3-D organoids generate complex organ-like tissues, however it is unclear how heterotypic interactions impact lineage identity. Here we use single-cell RNA-seq to reconstruct hepatocyte-like lineage progression from pluripotency in 2-D culture. We then derive 3-D liver bud (LB) organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during LB development. We find that LB hepatoblasts diverge from the 2-D lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark 3-D LBs against fetal and adult human liver scRNA-seq data, and find a striking correspondence between the 3-D LB and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signaling in LBs, and show that VEGF crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

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