scholarly journals Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Teresa G. Krieger ◽  
Solange Le Blanc ◽  
Julia Jabs ◽  
Foo Wei Ten ◽  
Naveed Ishaque ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Ductal Adenocarcinoma ◽  
Primary Tumors ◽  
Cell State ◽  
Tumor Subtypes ◽  
Functional Hierarchy ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that ‘classical’ and ‘basal-like’ cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, we identify distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. Cell states are connected by a differentiation hierarchy, with ‘classical’ cells concentrated at the endpoint. In an imaging-based drug screen, expression of ‘classical’ subtype genes correlates with better drug response. Our results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes, and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.

scholarly journals Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy

2020 ◽  
Author(s):  
Teresa G Krieger ◽  
Solange LeBlanc-Soto ◽  
Julia Jabs ◽  
Foo Wei Ten ◽  
Naveed Ishaque ◽  
...  
Keyword(s):  
Single Cell ◽  
Surface Proteins ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Patient Specific ◽  
Specific Expression ◽  
Primary Tumors ◽  
Cell State ◽  
Ductal Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ pancreatic tumors from ‘basal-like’ tumors with more aggressive clinical behaviour. We derived PDAC organoids from primary tumors of 18 patients, together with two matched samples from liver metastases. By single-cell RNA sequencing, we show that PDAC organoids consist of ductal cells with patient-specific expression of several gene groups, including genes which encode cell surface proteins. We report ‘classical’ and ‘basal-like’ cells coexisting within single primary tumors or metastases, with greater intratumor subtype heterogeneity linked to higher tumor grade. Single-cell transcriptome analysis of PDAC organoids and primary PDAC identified distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. We show that these cell states are connected by a differentiation hierarchy, with ‘classical’ subtype cells concentrated at the endpoint of this hierarchy. In an imaging-based drug screen, expression of ‘classical’ subtype genes also correlates with better response to clinical drugs. Our results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes, and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.

scholarly journals Mesenchymal Stromal Cells in the Bone Marrow Niche Consist of Multi-Populations With Distinct Transcriptional and Epigenetic Properties

2021 ◽  
Author(s):  
Sanshiro Kanazawa ◽  
Hironori Hojo ◽  
Shinsuke Ohba ◽  
Junichi Iwata ◽  
Makoto Komura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Single Cell ◽  
Expression Profiles ◽  
Marker Genes ◽  
Mouse Bone Marrow ◽  
Bone Marrow Niche ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract Although multiple studies have investigated the mesenchymal stem and progenitor cells (MSCs) that give rise to mature bone marrow, high heterogeneity in their morphologies and properties causes difficulties in molecular separation of their distinct populations. In this study, by taking advantage of the resolution of the single cell transcriptome, we analyzed Sca-1 and PDGFR-α fraction in the mouse bone marrow tissue. The single cell transcriptome enabled us to further classify the population into seven populations according to their gene expression profiles. We then separately obtained the seven populations based on candidate marker genes, and specified their gene expression properties and epigenetic landscape by ATAC-seq. Our findings will enable to elucidate the stem cell niche signal in the bone marrow microenvironment, reconstitute bone marrow in vitro, and shed light on the potentially important role of identified subpopulation in various clinical applications to the treatment of bone- and bone marrow-related diseases.

scholarly journals Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development

2020 ◽  
Vol 6 (34) ◽  
pp. eaaz2978 ◽  
Author(s):  
Xiaoying Fan ◽  
Yuanyuan Fu ◽  
Xin Zhou ◽  
Le Sun ◽  
Ming Yang ◽  
...  
Keyword(s):  
Single Cell ◽  
Neural Progenitor Cells ◽  
Neuronal Development ◽  
Single Cell Analysis ◽  
Cortical Development ◽  
Cell Lineage ◽  
Transcriptome Profiling ◽  
Developmental Trajectory ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Neurogenesis processes differ in different areas of the cortex in many species, including humans. Here, we performed single-cell transcriptome profiling of the four cortical lobes and pons during human embryonic and fetal development. We identified distinct subtypes of neural progenitor cells (NPCs) and their molecular signatures, including a group of previously unidentified transient NPCs. We specified the neurogenesis path and molecular regulations of the human deep-layer, upper-layer, and mature neurons. Neurons showed clear spatial and temporal distinctions, while glial cells of different origins showed development patterns similar to those of mice, and we captured the developmental trajectory of oligodendrocyte lineage cells until the human mid-fetal stage. Additionally, we verified region-specific characteristics of neurons in the cortex, including their distinct electrophysiological features. With systematic single-cell analysis, we decoded human neuronal development in temporal and spatial dimensions from GW7 to GW28, offering deeper insights into the molecular regulations underlying human neurogenesis and cortical development.

scholarly journals Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates

2021 ◽  
Author(s):  
Davide Simone ◽  
Frank Penkava ◽  
Anna Ridley ◽  
Stephen Nicholas Sansom ◽  
Hussein Mohamed Al-Mossawi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Single Cell ◽  
Cell Fate ◽  
Single Cell Analysis ◽  
Expression Patterns ◽  
Treg Subset ◽  
Inflammatory Site ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

scholarly journals Dissecting transition cells from single-cell transcriptome data through multiscale stochastic dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peijie Zhou ◽  
Shuxiong Wang ◽  
Tiejun Li ◽  
Qing Nie
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Stochastic Dynamics ◽  
Coarse Grained ◽  
State Transitions ◽  
Rate Theory ◽  
Transcriptome Data ◽  
Cell State ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractAdvances in single-cell technologies allow scrutinizing of heterogeneous cell states, however, detecting cell-state transitions from snap-shot single-cell transcriptome data remains challenging. To investigate cells with transient properties or mixed identities, we present MuTrans, a method based on multiscale reduction technique to identify the underlying stochastic dynamics that prescribes cell-fate transitions. By iteratively unifying transition dynamics across multiple scales, MuTrans constructs the cell-fate dynamical manifold that depicts progression of cell-state transitions, and distinguishes stable and transition cells. In addition, MuTrans quantifies the likelihood of all possible transition trajectories between cell states using coarse-grained transition path theory. Downstream analysis identifies distinct genes that mark the transient states or drive the transitions. The method is consistent with the well-established Langevin equation and transition rate theory. Applying MuTrans to datasets collected from five different single-cell experimental platforms, we show its capability and scalability to robustly unravel complex cell fate dynamics induced by transition cells in systems such as tumor EMT, iPSC differentiation and blood cell differentiation. Overall, our method bridges data-driven and model-based approaches on cell-fate transitions at single-cell resolution.

scholarly journals Progress in Single Cell Sequencing Technology

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Qi Cai Ma ◽  
Wen Li Wu ◽  
Na Ye ◽  
Xin Dong Wang ◽  
Ping Yan ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Basic Unit ◽  
Sequencing Technology ◽  
Single Cell Sequencing ◽  
Physiological Diversity ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Whole Transcriptome ◽  
Life Structure

Cells are the basic unit of life structure and life activities. Because of the complex micro-environment of cells, the content of components that play a key role is relatively small, so single-cell analysis is extremely challenging. In recent years, single-cell sequencing technology has been developed and matured. Single-cell sequencing can reveal the composition and physiological diversity of cells, and the existing single-cell separation technology, single-cell whole genome amplification technology, single The principles and applications of cell whole transcriptome amplification technology and single cell transcriptome sequencing are summarized and summarized.

scholarly journals Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Davide Simone ◽  
Frank Penkava ◽  
Anna Ridley ◽  
Stephen Sansom ◽  
M. Hussein Al-Mossawi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Single Cell ◽  
Cell Fate ◽  
Single Cell Analysis ◽  
Expression Patterns ◽  
Treg Subset ◽  
Inflammatory Site ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractRegulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

scholarly journals Single-cell transcriptome analysis reveals cell-cell communication and thyrocyte diversity in the zebrafish thyroid gland

2020 ◽  
Author(s):  
Pierre Gillotay ◽  
Meghna Shankar ◽  
Benoit Haerlingen ◽  
Sema Elif Eski ◽  
Macarena Pozo-Morales ◽  
...  
Keyword(s):  
Thyroid Gland ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Lymphatic Vessels ◽  
Cell Communication ◽  
Transcriptional Signature ◽  
Latent Heterogeneity ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Homogenous Population

AbstractThe thyroid gland regulates growth and metabolism via production of thyroid hormone in follicles composed of thyrocytes. So far, thyrocytes have been assumed to be a homogenous population. To uncover genetic heterogeneity in the thyrocyte population, and molecularly characterize the non-thyrocyte cells surrounding the follicle, we developed a single-cell transcriptome atlas of the zebrafish thyroid gland. The 6249-cell atlas includes profiles of thyrocytes, blood vessels, lymphatic vessels, immune cells and fibroblasts. Further, the thyrocytes could be split into two sub-populations with unique transcriptional signature, including differential expression of the transcription factor pax2a. To validate thyrocyte heterogeneity, we generated a CRISPR/Cas9-based pax2a knock-in line, which demonstrated specific pax2a expression in the thyrocytes. However, a population of pax2a-low mature thyrocytes interspersed within individual follicles could be distinguished, corroborating heterogeneity within the thyrocyte population. Our results identify and validate transcriptional differences within the nominally homogenous thyrocyte population.One-line summarySingle-cell analysis uncovers latent heterogeneity in thyroid follicular cells.Graphical Abstract

scholarly journals Mesenchymal stromal cells in the bone marrow niche consist of multi-populations with distinct transcriptional and epigenetic properties

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sanshiro Kanazawa ◽  
Hiroyuki Okada ◽  
Hironori Hojo ◽  
Shinsuke Ohba ◽  
Junichi Iwata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Single Cell ◽  
Expression Profiles ◽  
Marker Genes ◽  
Mouse Bone Marrow ◽  
Bone Marrow Niche ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractAlthough multiple studies have investigated the mesenchymal stem and progenitor cells (MSCs) that give rise to mature bone marrow, high heterogeneity in their morphologies and properties causes difficulties in molecular separation of their distinct populations. In this study, by taking advantage of the resolution of the single cell transcriptome, we analyzed Sca-1 and PDGFR-α fraction in the mouse bone marrow tissue. The single cell transcriptome enabled us to further classify the population into seven populations according to their gene expression profiles. We then separately obtained the seven populations based on candidate marker genes, and specified their gene expression properties and epigenetic landscape by ATAC-seq. Our findings will enable to elucidate the stem cell niche signal in the bone marrow microenvironment, reconstitute bone marrow in vitro, and shed light on the potentially important role of identified subpopulation in various clinical applications to the treatment of bone- and bone marrow-related diseases.

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