Adaptable durable human endothelial cells for organogenesis and tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA542371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9042770_1.fastq.gz | Fastqsanger.gz | |||
| SRR9042770_2.fastq.gz | Fastqsanger.gz | |||
| SRR9042780_1.fastq.gz | Fastqsanger.gz | |||
| SRR9042780_2.fastq.gz | Fastqsanger.gz | |||
| SRR9042790_1.fastq.gz | Fastqsanger.gz |
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Project description:Adaptable durable human endothelial cells for organogenesis and tumorigenesis
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Project description:Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.
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Project description:During early mouse embryonic development, pluripotent cells rapidly divide and diversify to construct the developing foetus, yet the underlying regulatory programs that define the cell repertoire for each organ remain ill-defined. To delineate comprehensive chromatin landscapes of mammalian lineages during early organogenesis, we mapped chromatin accessibility in 19,453 single nuclei from mouse embryos collected at 8.25 days post-fertilisation. Identification of cell type-specific regions of open chromatin pinpointed known regulatory regions and two new TAL1-bound endothelial enhancers, which we validated using transgenic mouse assays. Integrated gene expression and transcription factor motif enrichment analyses highlighted known and previously unrecognised cell type-specific transcriptional regulators. Subsequent in vivo experiments in zebrafish revealed a powerful role for the ETS transcription factor FEV in endothelial identity. Concerted in vivo validation experiments in mouse and zebrafish thus illustrate how single-cell open chromatin maps, representative of a mammalian embryo, provide access to the regulatory blueprint for mammalian organogenesis.
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Project description:Background: Organogenesis is crucial for proper organ formation during mammalian embryonic development. However, the similarities and shared features between different organs and the cellular heterogeneity during this process at single-cell resolution remain elusive. Results: We perform single-cell RNA sequencing analysis of 1,916 individual cells from eight organs and tissues of E9.5 to E11.5 mouse embryos, namely, the forebrain, hindbrain, skin, heart, somite, lung, liver, and intestine. Based on the regulatory activities rather than the expression patterns, all cells analyzed can be well classified into four major groups with epithelial, mesodermal, hematopoietic and neuronal identities. For different organs within the same group, the similarities and differences of their features and developmental paths are revealed and reconstructed. Conclusions: We identify mutual interactions between epithelial and mesenchymal cells and detect epithelial cells with prevalent mesenchymal features during organogenesis, which are similar to the features of intermediate epithelial/mesenchymal cells during tumorigenesis. The comprehensive transcriptome at single-cell resolution profiled in our study paves the way for future mechanistic studies of the gene- regulatory networks governing mammalian organogenesis.
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