Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Glia ◽  
2020 ◽  
Vol 68 (6) ◽  
pp. 1291-1303 ◽  
Author(s):  
Kelly Perlman ◽  
Charles P. Couturier ◽  
Moein Yaqubi ◽  
Arnaud Tanti ◽  
Qiao‐Ling Cui ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Progenitor Cells ◽  
Rna Sequencing ◽  
Developmental Trajectory ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Single Cell Rna Sequencing

scholarly journals Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lanqi Gong ◽  
Dora Lai-Wan Kwong ◽  
Wei Dai ◽  
Pingan Wu ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Single Cell ◽  
Rna Sequencing ◽  
Progression Free Survival ◽  
Developmental Trajectory ◽  
Free Survival ◽  
Genetic Profiling ◽  
Single Cell Rna Sequencing ◽  
Infiltrating Cells ◽  
Patient Prognosis

AbstractThe tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.

Abstract 305: Single Cell RNA Sequencing of Adult Cardiac c-kit+ Cells in a Murine Lineage Tracing Model

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Bryan D Maliken ◽  
Onur Kanisicak ◽  
Jeffery D Molkentin
Keyword(s):  
Single Cell ◽  
Progenitor Cells ◽  
Rna Sequencing ◽  
Cardiac Injury ◽  
Mesenchymal Cells ◽  
Lineage Tracing ◽  
Tyrosine Kinase Receptor ◽  
Early Differentiation ◽  
Gfp Reporter ◽  
Single Cell Rna Sequencing

A subset of adult cardiac resident cells defined by the stem cell factor tyrosine kinase receptor termed c-kit, are believed to have myogenic potential and are now being delivered via intracoronary infusion to presumably promote cardiac regeneration and improve ventricular function after ischemic cardiac injury. However, recent studies have shown that despite these benefits, c-kit+ progenitor cells in the adult murine heart are more inclined to take on an endothelial rather than cardiomyocyte lineage. To better define the factors involved in early differentiation of these resident cardiac progenitor cells and to distinguish distinct cell subpopulations, we performed single cell RNA sequencing on c-kit+ cells from Kit-Cre lineage traced GFP reporter mice versus total mesenchymal cells from the heart that were CD31- and CD45-. Cells were isolated by cardiac digestion and FACS was performed, positively sorting for the c-kit+ lineage while negatively sorting for CD31 and CD45 to eliminate endothelial and leukocyte progenitor contamination, respectively. Following this isolation, cells were examined to determine GFP reporter status and then submitted for single cell RNA sequencing using the Fluidigm A1 system. Clustering of 654 genes from this data identified 6 distinct subpopulations indicating various stages of early differentiation among CD31- and CD45-negative cardiac interstitial cells. Furthermore, comparison of GFP+ c-kit cells to the total non-GFP mesenchymal cells identified 75 differentially expressed transcripts. These unique gene signatures may help parse the genes that underlie cellular plasticity in the heart and define the best molecular lineages for transdifferentiation into cardiac myocytes.

Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing

Cephalalgia ◽  
2018 ◽  
Vol 38 (13) ◽  
pp. 1976-1983 ◽  
Author(s):  
William Renthal
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Cell Types ◽  
Susceptibility Genes ◽  
Brain Cell ◽  
Cell Type ◽  
Single Cell Rna Sequencing ◽  
Brain Cell Types

Background Migraine is a debilitating disorder characterized by severe headaches and associated neurological symptoms. A key challenge to understanding migraine has been the cellular complexity of the human brain and the multiple cell types implicated in its pathophysiology. The present study leverages recent advances in single-cell transcriptomics to localize the specific human brain cell types in which putative migraine susceptibility genes are expressed. Methods The cell-type specific expression of both familial and common migraine-associated genes was determined bioinformatically using data from 2,039 individual human brain cells across two published single-cell RNA sequencing datasets. Enrichment of migraine-associated genes was determined for each brain cell type. Results Analysis of single-brain cell RNA sequencing data from five major subtypes of cells in the human cortex (neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells) indicates that over 40% of known migraine-associated genes are enriched in the expression profiles of a specific brain cell type. Further analysis of neuronal migraine-associated genes demonstrated that approximately 70% were significantly enriched in inhibitory neurons and 30% in excitatory neurons. Conclusions This study takes the next step in understanding the human brain cell types in which putative migraine susceptibility genes are expressed. Both familial and common migraine may arise from dysfunction of discrete cell types within the neurovascular unit, and localization of the affected cell type(s) in an individual patient may provide insight into to their susceptibility to migraine.

scholarly journals 973. Single-cell RNA Sequencing Analysis of Zika Virus Infection in Human Stem Cell-Derived Cerebral Organoids

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S33-S34
Author(s):  
Karen Ocwieja ◽  
Alexandra Stanton ◽  
Alexsia Richards ◽  
Jenna Antonucci ◽  
Travis Hughes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Single Cell ◽  
Rna Sequencing ◽  
Zika Virus ◽  
Model Systems ◽  
Sequencing Analysis ◽  
Human Stem Cell ◽  
Zikv Infection ◽  
Single Cell Rna Sequencing

Abstract Background The molecular mechanisms underpinning the neurologic and congenital pathologies caused by Zika virus (ZIKV) infection remain poorly understood. One barrier has been the lack of relevant model systems for the developing human brain; however, thanks to advances in the stem cell field, we can now evaluate ZIKV central nervous system infections in human stem cell-derived cerebral organoids which recapitulate complex 3-dimensional neural architecture. Methods We apply Seq-Well—a simple, portable platform for massively parallel single-cell RNA sequencing—to characterize cerebral organoids infected with ZIKV. Using this sequencing method, and published transcriptional profiles, we identify multiple cellular populations in our organoids, including neuroprogenitor cells, intermediate progenitor cells, and terminally differentiated neurons. We detect and quantify host mRNA transcripts and viral RNA with single-cell resolution, defining transcriptional features of uninfected cells and infected cells. Results In this model of the developing brain, we identify preferred tropisms of ZIKV infection and pronounced effects on cell division, differentiation, and death. Our data additionally reveal differences in cellular populations and gene expression within organoids infected by historic and contemporary ZIKV strains from a variety of geographic locations. This finding might help explain phenotypic differences attributed to the viruses, including variable propensity to cause microcephaly. Conclusion Overall, our work provides insight into normal and diseased human brain development, and suggests that both virus replication and host response mechanisms underlie the neuropathology of ZIKV infection. Disclosures All Authors: No reported Disclosures.

scholarly journals A survey of human brain transcriptome diversity at the single cell level

2015 ◽  
Vol 112 (23) ◽  
pp. 7285-7290 ◽  
Author(s):  
Spyros Darmanis ◽  
Steven A. Sloan ◽  
Ye Zhang ◽  
Martin Enge ◽  
Christine Caneda ◽  
...  
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cortical Neurons ◽  
Cell Types ◽  
Type I ◽  
Neuronal Populations ◽  
Brain Transcriptome ◽  
Single Cell Rna Sequencing ◽  
Whole Transcriptome

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain.

scholarly journals Heterogeneity of oligodendrocyte progenitor cells in adult human brain

2014 ◽  
Vol 1 (4) ◽  
pp. 272-283 ◽  
Author(s):  
Soo Yuen Leong ◽  
Vijayaraghava T. S. Rao ◽  
Jenea M. Bin ◽  
Pavel Gris ◽  
Mugundhine Sangaralingam ◽  
...  
Keyword(s):  
Human Brain ◽  
Progenitor Cells ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Adult Human Brain ◽  
Adult Human

scholarly journals Temporal single-cell transcriptomes of zebrafish spinal cord pMN progenitors reveal distinct neuronal and glial progenitor populations

2021 ◽  
Author(s):  
Kayt Scott ◽  
Rebecca O’Rourke ◽  
Caitlin C. Winkler ◽  
Christina A. Kearns ◽  
Bruce Appel
Keyword(s):  
Spinal Cord ◽  
Transcription Factor ◽  
Single Cell ◽  
Progenitor Cells ◽  
Rna Sequencing ◽  
Motor Neurons ◽  
Marker Genes ◽  
List Type ◽  
Fate Mapping ◽  
Single Cell Rna Sequencing

AbstractVentral spinal cord progenitor cells, which express the basic helix loop helix transcription factor Olig2, sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Following specification some OPCs differentiate as myelinating oligodendrocytes while others persist as OPCs. Though a considerable amount of work has described the molecular profiles that define motor neurons, OPCs, and oligodendrocytes, less is known about the progenitors that produce them. To identify the developmental origins and transcriptional profiles of motor neurons and OPCs, we performed single-cell RNA sequencing on isolated pMN cells from embryonic zebrafish trunk tissue at stages that encompassed motor neurogenesis, OPC specification, and initiation of oligodendrocyte differentiation. Downstream analyses revealed two distinct pMN progenitor populations: one that appears to produce neurons and one that appears to produce OPCs. This latter population, called Pre-OPCs, is marked by expression of GS Homeobox 2 (gsx2), a gene that encodes a homeobox transcription factor. Using fluorescent in situ hybridizations, we identified gsx2-expressing Pre-OPCs in the spinal cord prior to expression of canonical OPC marker genes. Our data therefore reveal heterogeneous gene expression profiles among pMN progenitors, supporting prior fate mapping evidence.HighlightsSingle-cell RNA sequencing reveals the developmental trajectories of neurons and glia that arise from spinal cord pMN progenitor cells in zebrafish embryosTranscriptionally distinct subpopulations of pMN progenitors are the apparent sources of neurons or oligodendrocytes, consistent with fate mapping datagsx2 expression marks pMN progenitors that produce oligodendrocyte lineage cells

Landscape of Cell Heterogeneity and Evolutionary Trajectory in Ulcerative Colitis-associated Colon Cancer Revealed by Single-cell Rna Sequencing

2020 ◽  
Author(s):  
Quan Wang ◽  
Zhu Wang ◽  
Zhen Zhang ◽  
Wei Zhang ◽  
Mengmeng Zhang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Colon Cancer ◽  
Single Cell ◽  
Rna Sequencing ◽  
Developmental Trajectory ◽  
The Cancer Genome Atlas ◽  
Cell Heterogeneity ◽  
Evolutionary Trajectory ◽  
Cell Clusters ◽  
Single Cell Rna Sequencing

Abstract Background: Patients with colitis-associated cancer (CAC), a particular kind of colorectal cancer that develops from inflammatory bowel diseases (IBDs), have an earlier morbidity and a poorer prognosis. However, in CAC, single cell transcriptome analysis of the microenvironment composition and characteristics has yet to be performed. To understand the intra-tumor heterogeneity in CAC and to reveal a potential evolutionary trajectory from ulcerative colitis (UC) to CAC at the single cell level. Methods: Fresh samples of tumor- and adjacent tissue, from a CAC patient with pT3N1M0, were examined by single cell RNA sequencing (scRNA-seq). Data from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with prognosis. Results: Ultimately, 4,777 single-cell transcriptomes (1220 genes per cell) were studied, which composed of 2,250 (47%) and 2,527(53%) originated from tumor- and non-malignant tissue, respectively. And we defined the composition of cancer-associated stromal cells and identified six cell clusters included myeloid, T and B cells, fibroblasts, endothelial and epithelial cells. Likewise, the notable pathways and transcription factors (TFs) involved of these cell clusters were analyzed and described. Moreover, we graphed the precise cellular composition and developmental trajectory from UC to UC-associated colon cancer, and predicted that CD74, CLCA1 and DPEP1 had a potential role in the disease progression. Conclusions: scRNA-seq technology could reveal intratumor cell heterogeneity in ulcerative colitis-associated colon cancer, and might provide a promising direction to seek the novel potential therapeutic targets in the evolution from IBD to CAC.

scholarly journals Single-cell RNA-sequencing identifies the developmental trajectory of C-Myc-dependent NK1.1− T-bet+ intraepithelial lymphocyte precursors

2019 ◽  
Vol 13 (2) ◽  
pp. 257-270 ◽  
Author(s):  
Jonas F. Hummel ◽  
Patrice Zeis ◽  
Karolina Ebert ◽  
Jonas Fixemer ◽  
Philip Konrad ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Intraepithelial Lymphocytes ◽  
Developmental Trajectory ◽  
High Avidity ◽  
Clonal Deletion ◽  
Adaptive Immune Cells ◽  
Single Cell Rna Sequencing ◽  
Factor C

Abstract Natural intraepithelial lymphocytes (IELs) are thymus-derived adaptive immune cells, which are important contributors to intestinal immune homeostasis. Similar to other innate-like T cells, they are induced in the thymus through high-avidity interaction that would otherwise lead to clonal deletion in conventional CD4 and CD8 T cells. By applying single-cell RNA-sequencing (scRNA-seq) on a heterogeneous population of thymic CD4−CD8αβ−TCRαβ+NK1.1− IEL precursors (NK1.1− IELPs), we define a developmental trajectory that can be tracked based on the sequential expression of CD122 and T-bet. Moreover, we identify the Id proteins Id2 and Id3 as a novel regulator of IELP development and show that all NK1.1− IELPs progress through a PD-1 stage that precedes the induction of T-bet. The transition from PD-1 to T-bet is regulated by the transcription factor C-Myc, which has far reaching effects on cell cycle, energy metabolism, and the translational machinery during IELP development. In summary, our results provide a high-resolution molecular framework for thymic IEL development of NK1.1− IELPs and deepen our understanding of this still elusive cell type.

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