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| Status |
Public on May 12, 2023 |
| Title |
Incongruence between transcriptional and vascular pathophysiological cell states I |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or the ligand Dll4 induces angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTor, had no effect on the vascular expansion induced by Dll4 loss, however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes, and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.
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| Overall design |
Liver endothelial cells of the Cdh5-CreERT2 + iSuRe-Cre mice (with or without different floxed alleles) were isolated by Fluorescence-activated cell sorting (FACS) according to their CD31+ (ECs) profile and the presence of iSuRe-Cre reporter Tomato signal (induced by Cdh5-CreERT2 - expressed only in ECs). These cells were analyzed using scRNA-seq.
Liver non Endothelial Cells of the Cdh5-CreERT2 + iSuRe-Cre mice were isolated by Fluorescence-activated cell sorting (FACS) after gating on the CD31Negative population with varying levels of CD45 (Neg, Lo and Hi) and analyzed using scRNAseq.
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| Web link |
https://doi.org/10.1038/s44161-023-00272-4
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| Contributor(s) |
Regano Á, Torroja C, Fernández-Chacón M, Mühleder S, Garcia-Ortega L, Rocha SF, Sanchez-Muñoz MS, Lytvyn M, Casquero-Garcia V, De Andrés-Laguillo M, Muhl L, Orlich MM, Gaengel K, Camafeita E, Vazquez J, Benguría A, Iruela-Arispe M, Dopazo A, Sánchez-Cabo F, Carter H, Benedito R |
| Citation(s) |
37745941 |
| Submission date |
Apr 14, 2023 |
| Last update date |
Oct 03, 2023 |
| Contact name |
Rui Benedito |
| E-mail(s) |
rui.benedito@cnic.es
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| Organization name |
CNIC
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| Department |
3N
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| Lab |
Molecular Genetics of Angiogenesis
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| Street address |
C. de Melchor Fernández Almagro, 3
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| City |
Madrid |
| State/province |
Madrid |
| ZIP/Postal code |
28029 |
| Country |
Spain |
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| Platforms (2) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL30172 |
NextSeq 2000 (Mus musculus) |
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| Samples (10)
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| GSM7177823 |
Liver_1_GEX_CD31+_ECs_scRNASeq_Control_Dll4iDEC_Notch1iDEC_RbpjiDEC |
| GSM7177824 |
Liver_1_HTO |
| GSM7177825 |
Liver_2_GEX_CD31+ECs _Control_DBZ_Dll4iDEC+Anti-VEGF_ Notch1/2/4iDEC_ Dll4 HETiDEC |
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| This SubSeries is part of SuperSeries: |
| GSE231613 |
Incongruence between transcriptional and vascular pathophysiological cell states |
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| Relations |
| BioProject |
PRJNA955832 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE229793_Liver_1.barcodes.tsv.gz |
27.1 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_1.features.tsv.gz |
284.2 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_1.matrix.mtx.gz |
52.3 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_2.barcodes.tsv.gz |
115.9 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_2.features.tsv.gz |
284.2 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_2.matrix.mtx.gz |
210.5 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_3.barcodes.tsv.gz |
64.5 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_3.features.tsv.gz |
284.2 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_3.matrix.mtx.gz |
83.1 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_4.barcodes.tsv.gz |
46.9 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_4.features.tsv.gz |
284.2 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_4.matrix.mtx.gz |
65.0 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_non_ECs_Ctl_barcodes.tsv.gz |
7.6 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_non_ECs_Ctl_features.tsv.gz |
187.3 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_non_ECs_Ctl_matrix.mtx.gz |
10.7 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_non_ECs_Dll4LOF_barcodes.tsv.gz |
19.3 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_non_ECs_Dll4LOF_features.tsv.gz |
187.3 Kb |
(ftp)(http) |
TSV |
| GSE229793_Liver_non_ECs_Dll4LOF_matrix.mtx.gz |
28.6 Mb |
(ftp)(http) |
MTX |
| GSE229793_Liver_non_ECs_expression_matrix.csv.gz |
7.6 Mb |
(ftp)(http) |
CSV |
| GSE229793_Liver_non_ECs_metadata.csv.gz |
134.1 Kb |
(ftp)(http) |
CSV |
| GSE229793_expression_matrix.csv.gz |
31.4 Mb |
(ftp)(http) |
CSV |
| GSE229793_genes.gtf.gz |
31.7 Mb |
(ftp)(http) |
GTF |
| GSE229793_genome.fa.fai.txt.gz |
875 b |
(ftp)(http) |
TXT |
| GSE229793_genome.fa.gz |
769.1 Mb |
(ftp)(http) |
FA |
| GSE229793_metadata.csv.gz |
225.9 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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