Adaptable durable human endothelial cells for organogenesis and tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA616300 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11452375.fastq.gz | Fastqsanger.gz | |||
| SRR11452376.fastq.gz | Fastqsanger.gz | |||
| SRR11452377.fastq.gz | Fastqsanger.gz | |||
| SRR11452378.fastq.gz | Fastqsanger.gz | |||
| SRR11452379.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:We here report transcriptome profiling of human embryos at six successive developmental stages (i.e., Carnegie Stages 9 to 14), representing the first comprehensive gene expression database of early human organogenesis. Through a series of data mining and comparisons with the transcriptome during mouse embryogenesis and the disparate genomic data in human embryonic stem cells, we revealed that development potential during early human organogenesis is orchestrated by two dominant categories of genes. Specifically, most gradually induced genes are largely differentiation related whereas those gradually repressed are involved in both stemness- and differentiation-relevant aspects of the developmental potential. Further through integrative mining we uncovered a molecular network that well characterizes stemness- and differentiation-relevant aspects of developmental potentials during early human organogenesis. Analysis of published data showed that the network could serve to evaluate various differentiation models. Our results make a significant step towards understanding of human embryogenesis at a molecular level and suggest that developmental potentials are under control of shared regulatory events. With the consent of subjects and of the Ethical Review Board of the Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine,we collected human post-implantation embryos at six successive time periods: Carnegie Stages 9 to 14 (E20 to E32), covering the first third of organogenesis. Using the Affymetrix HG-U133A Genechip microarrays, three replicates were independently profiled for each stage to minimize the influence of the embryo-to-embryo variation. Raw expression data were normalized using Robust Multi-array Averaging (RMA) with quantile normalization. The resultant expression data were imported into Extraction of Differential Gene Expression (EDGE) software for the detection of probesets exhibiting the consistent changes within the triplicates and differential expression (denoted as hORG expression matrix). The hORG expression matrix was subjected to Linear Models for Microarray Data (LIMMA) bioconductor library for identification of stage-transitive transcriptome changes, and self-organizing map combined with singular value decomposition (SOM-SVD) as well as SOM-based two-phase gene clustering for the topology-preserving extraction of temporal expression patterns. Hypergeometric distribution-based enrichment analyses were performed to explore the underlying biological relevance of gene groups of interest using diverse external annotated databases. The Cytoscape plug-in jActiveModules was modified to identify expression-active connected subnetworks in the compiled human interaction/association network.
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Project description:N6-methyladenosine (m6A) in mRNA is key to eukaryotic gene regulation. Many m6A functions involve RNA-binding proteins that recognize m6A via a YT521-B Homology (YTH) domain. YTH domain proteins contain long intrinsically disordered regions (IDRs) that may mediate phase separation and interaction with protein partners, but whose precise biochemical functions remain largely unknown. The Arabidopsis thaliana YTH domain proteins ECT2, ECT3 and ECT4 accelerate organogenesis through stimulation of cell division in organ primordia. Here, we use ECT2 to reveal molecular underpinnings of this function. We show that stimulation of leaf formation requires the long N-terminal IDR, and we identify two short IDR-elements required for ECT2-mediated organogenesis. Of these two, a 19-amino acid region containing a tyrosine-rich motif conserved in both plant and metazoan YTHDF proteins is necessary for binding to the major cytoplasmic poly(A)-binding proteins PAB2, PAB4 and PAB8. Remarkably, overexpression of PAB4 in leaf primordia partially rescues the delayed leaf formation in ect2 ect3 ect4 mutants, suggesting that the ECT2-PAB2/4/8 interaction on target mRNAs of organogenesis-related genes may overcome limiting PAB concentrations in primordial cells.
2023-11-28 | PXD045801 | Pride
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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