Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Xie, Yuan; He, Liqun; Lugano, Roberta; Zhang, Yanyu; Cao, Haiyan; He, Qiyuan; Chao, Min; Liu, Boxuan; Cao, Qingze; Wang, Jianhao; Jiao, Yang; Hu, Yibo; Han, Liying; Zhang, Yong; Huang, Hua; Uhrbom, Lene; Betsholtz, Christer; Wang, Liang; Dimberg, Anna; Zhang, Lei

doi:10.1172/jci.insight.150861

Cited by 81 publications

(98 citation statements)

References 35 publications

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“…Previous studies have shown that apln expression is highly expressed in endothelial tip cells, a type of endothelial cell found at the leading ends of sprouting vasculature that play a coordinating role in angiogenesis and vasculature organization in zebrafish (48,49). Furthermore, APLN has been shown to be expressed in sprouting vasculature, particularly in the context of injury or disease, in mice (50), and humans (51,52), indicating a conserved role for APLN across species. This scRNA-seq dataset presented here provides an atlas for the distinct transcriptional profiles of the cell types that comprise the adult zebrafish liver and establishes an important resource for utilizing zebrafish as a tool to study liver function and disease.…”

Section: Creation Of a Single Cell Atlas Of The Adult Zebrafish Livermentioning

confidence: 96%

Single-cell transcriptomic profiling of healthy and fibrotic adult zebrafish liver reveals conserved cell identities and stellate cell activation phenotypes with human liver

Morrison

DeRossi

Alter

et al. 2021

Preprint

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Liver fibrosis is the excessive accumulation of extracellular matrix that can progress to cirrhosis and failure if untreated (1). The mechanisms of fibrogenesis are multi-faceted and remain elusive with no approved antifibrotic treatments available (2). Here we use single-cell RNA sequencing (scRNA-seq) of the adult zebrafish liver to study the molecular and cellular dynamics of the liver at a single-cell level and demonstrate the value of the adult zebrafish as a model for studying liver fibrosis. scRNA-seq reveals transcriptionally unique populations of hepatic cell types that comprise the zebrafish liver. Joint clustering with human liver scRNA-seq data demonstrates high conservation of transcriptional profiles and human marker genes in zebrafish cell types. Human and zebrafish hepatic stellate cells (HSCs), the driver cell in liver fibrosis (3), specifically show conservation of transcriptional profiles and we uncover Colec11 as a novel, conserved marker for zebrafish HSCs. To demonstrate the power of scRNA-seq to study liver fibrosis, we performed scRNA-seq on our zebrafish model of a pediatric liver disease with characteristic early, progressive liver fibrosis caused by mutation in mannose phosphate isomerase (MPI) (4–6). Comparison of differentially expressed genes from human and zebrafish MPI mutant HSC datasets demonstrated similar activation of fibrosis signaling pathways and upstream regulators. CellPhoneDB analysis revealed important receptor-ligand interactions within normal and fibrotic states. This study establishes the first scRNA-seq atlas of the adult zebrafish liver, highlights the high degree of similarity to the human liver, and strengthens its value as a model to study liver fibrosis.Significance StatementTo our knowledge, this is the first single-cell characterization of the adult zebrafish liver, both in a normal physiologic state and in the setting of liver fibrosis. We identify transcriptionally distinct zebrafish liver cell populations and a high degree of transcriptional conservation between human and zebrafish cells across the majority of hepatic cell types. Furthermore, using this scRNA transcriptome, we identify key signaling pathways in zebrafish HSCs that are replicated in human HSCs and implicated in the regulation of liver fibrosis. Our work provides a useful resource that can be used to aid research using the zebrafish liver and asserts the usefulness of the adult zebrafish to study liver fibrosis.

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Section: Creation Of a Single Cell Atlas Of The Adult Zebrafish Livermentioning

confidence: 96%

Single-cell transcriptomic profiling of healthy and fibrotic adult zebrafish liver reveals conserved cell identities and stellate cell activation phenotypes with human liver

Morrison

DeRossi

Alter

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…This likely contributes to the poor T cell infiltration observed in GBM, as increased VEGF signaling in endothelial cells can reduce leukocyte recruitment by inhibiting the expression of adhesion molecules and chemokines required for T cell recruitment (28)(29)(30). Notably, vessel phenotype is heterogeneous in GBM and varies both between patients and within a single tumor (31). Single cell mRNA sequencing of endothelial cells isolated from human GBM demonstrated that while activated endothelial cells are detected in some patients, the majority of endothelial cells within the tumor are angiogenic and express low levels of adhesion molecules and chemokines (31).…”

Section: The Immune Microenvironment Of Gbmmentioning

confidence: 99%

“…Notably, vessel phenotype is heterogeneous in GBM and varies both between patients and within a single tumor ( 31 ). Single cell mRNA sequencing of endothelial cells isolated from human GBM demonstrated that while activated endothelial cells are detected in some patients, the majority of endothelial cells within the tumor are angiogenic and express low levels of adhesion molecules and chemokines ( 31 ).…”

Section: The Immune Microenvironment Of Gbmmentioning

confidence: 99%

Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma

et al. 2021

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Glioblastoma is the most common and aggressive brain tumor, which is uniformly lethal due to its extreme invasiveness and the absence of curative therapies. Immune checkpoint inhibitors have not yet proven efficacious for glioblastoma patients, due in part to the low prevalence of tumor-reactive T cells within the tumor microenvironment. The priming of tumor antigen-directed T cells in the cervical lymph nodes is complicated by the shortage of dendritic cells and lack of appropriate lymphatic vessels within the brain parenchyma. However, recent data suggest that naive T cells may also be primed within brain tumor-associated tertiary lymphoid structures. Here, we review the current understanding of the formation of these structures within the central nervous system, and hypothesize that promotion of tertiary lymphoid structures could enhance priming of tumor antigen-targeted T cells and sensitize glioblastomas to cancer immunotherapy.

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“…Single cell RNA sequencing datasets of ECs from GBM and paired non-malignant control brain tissue were downloaded from the Gene Expression Omnibus (GEO) database (GSE162631). Information for cells and samples were obtained in the previous study (4). Only ECs from peripheral endothelial cell type I (Pe1), tumor core endothelial cell type I (Co1) and tumor core endothelial cell type II (Co2), which were represented in four patients, in the original study were selected for downstream analysis.…”

Section: Bioinformatics Analysis Of Ets1 Expression In Ecsmentioning

confidence: 99%

“…Microvascular proliferation and abnormal vasculature are the hallmarks of GBM (2,3). Endothelial cells (ECs) in GBM vessels are associated with a distinct gene signature characterized by upregulation of genes involved in basement membrane remodelling, cytoskeletal rearrangements, angiogenic sprouting and tip cell formation (4). Vascular abnormality aggravates GBM progression by promoting tumor cell invasiveness through inducing hypoxia (5,6).…”

Section: Introductionmentioning

confidence: 99%

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma

Tang¹,

Li²,

Liu³

et al. 2021

Pathol. Oncol. Res.

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Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFβ signaling, and targeting TGFβ signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFβ inhibition may suppress the vascular abnormality driven by ETS1.

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Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing

Cited by 81 publications

References 35 publications

Single-cell transcriptomic profiling of healthy and fibrotic adult zebrafish liver reveals conserved cell identities and stellate cell activation phenotypes with human liver

Single-cell transcriptomic profiling of healthy and fibrotic adult zebrafish liver reveals conserved cell identities and stellate cell activation phenotypes with human liver

Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma

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