scholarly journals Single-Cell RNA Sequencing Defines the Regulation of Spermatogenesis by Sertoli-Cell Androgen Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Congcong Cao ◽  
Qian Ma ◽  
Shaomei Mo ◽  
Ge Shu ◽  
Qunlong Liu ◽  
...  
Keyword(s):  
Single Cell ◽  
Sertoli Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Wild Type ◽  
Cellular Processes ◽  
Transcriptomic Sequencing ◽  
Transcriptional Changes

Androgen receptor (AR) signaling is essential for maintaining spermatogenesis and male fertility. However, the molecular mechanisms by which AR acts between male germ cells and somatic cells during spermatogenesis have not begun to be revealed until recently. With the advances obtained from the use of transgenic mice lacking AR in Sertoli cells (SCARKO) and single-cell transcriptomic sequencing (scRNA-seq), the cell specific targets of AR action as well as the genes and signaling pathways that are regulated by AR are being identified. In this study, we collected scRNA-seq data from wild-type (WT) and SCARKO mice testes at p20 and identified four somatic cell populations and two male germ cell populations. Further analysis identified that the distribution of Sertoli cells was completely different and uncovered the cellular heterogeneity and transcriptional changes between WT and SCARKO Sertoli cells. In addition, several differentially expressed genes (DEGs) in SCARKO Sertoli cells, many of which have been previously implicated in cell cycle, apoptosis and male infertility, have also been identified. Together, our research explores a novel perspective on the changes in the transcription level of various cell types between WT and SCARKO mice testes, providing new insights for the investigations of the molecular and cellular processes regulated by AR signaling in Sertoli cells.

scholarly journals The single-cell epigenetic regulatory landscape in mammalian perinatal testis development

2021 ◽  
Author(s):  
Jinyue Liao ◽  
Hoi Ching Suen ◽  
Shitao Rao ◽  
Alfred Chun Shui Luk ◽  
Ruoyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Cell Type

AbstractSpermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution data also revealed putative stem cells within the Sertoli and Leydig cell populations. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the ‘regulon’ of the mouse male germline and supporting somatic cells.

scholarly journals Single-Cell Genomics: Catalyst for Cell Fate Engineering

2021 ◽  
Vol 9 ◽  
Author(s):  
Boxun Li ◽  
Gary C. Hon
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
State Transitions ◽  
Small Scale ◽  
Specific Cell ◽  
Direct Reprogramming ◽  
Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

scholarly journals Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

2019 ◽  
Author(s):  
Soumya Korrapati ◽  
Ian Taukulis ◽  
Rafal Olszewski ◽  
Madeline Pyle ◽  
Shoujun Gu ◽  
...  
Keyword(s):  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Stria Vascularis ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Genetic Mechanisms ◽  
Single Nucleus ◽  
Gene Regulatory

AbstractThe stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

scholarly journals Single-cell Transcriptomics Identify Extensive Heterogeneity in the Cellular Composition of Mouse Achilles Tendons

2019 ◽  
Author(s):  
Andrea J De Micheli ◽  
Jacob B Swanson ◽  
Nathaniel P Disser ◽  
Leandro M Martinez ◽  
Nicholas R Walker ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Tissue Homeostasis ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Cellular Composition ◽  
Matrix Assembly ◽  
Distinct Cell ◽  
Single Cell Rna Sequencing ◽  
Additional Support

AbstractTendon is a connective tissue that transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, but little is known about the diversity of cells that populate tendon. Our objective was to explore the heterogeneity of cells in mouse Achilles tendons using single-cell RNA sequencing. We assembled a transcriptomic atlas and identified 11 distinct cell types in tendons, including 3 previously undescribed populations of fibroblasts. Using trajectory inference analysis, we provide additional support for the notion that pericytes are progenitor cells for the fibroblasts that compose adult tendons. We also modeled cell-interactions and identified ligand-receptor pairs involved in tendon homeostasis. Our findings highlight notable heterogeneity between and within tendon cell populations, which may contribute to our understanding of tendon extracellular matrix assembly and maintenance, and inform the design of therapies to treat tendinopathies.

scholarly journals Single-cell transcriptome profiling of the vaginal wall in women with severe anterior vaginal prolapse

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yaqian Li ◽  
Qing-Yang Zhang ◽  
Bao-Fa Sun ◽  
Yidi Ma ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Single Cell ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cell Communication ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Vaginal Wall ◽  
Vaginal Prolapse ◽  
Cellular Heterogeneity ◽  
Anterior Vaginal Prolapse

AbstractAnterior vaginal prolapse (AVP) is the most common form of pelvic organ prolapse (POP) and has deleterious effects on women’s health. Despite recent advances in AVP diagnosis and treatment, a cell atlas of the vaginal wall in AVP has not been constructed. Here, we employ single-cell RNA-seq to construct a transcriptomic atlas of 81,026 individual cells in the vaginal wall from AVP and control samples and identify 11 cell types. We reveal aberrant gene expression in diverse cell types in AVP. Extracellular matrix (ECM) dysregulation and immune reactions involvement are identified in both non-immune and immune cell types. In addition, we find that several transcription factors associated with ECM and immune regulation are activated in AVP. Furthermore, we reveal dysregulated cell–cell communication patterns in AVP. Taken together, this work provides a valuable resource for deciphering the cellular heterogeneity and the molecular mechanisms underlying severe AVP.

scholarly journals Single-cell transcriptomic analysis identifies extensive heterogeneity in the cellular composition of mouse Achilles tendons

2020 ◽  
Vol 319 (5) ◽  
pp. C885-C894 ◽  
Author(s):  
Andrea J. De Micheli ◽  
Jacob B. Swanson ◽  
Nathaniel P. Disser ◽  
Leandro M. Martinez ◽  
Nicholas R. Walker ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Matrix Assembly ◽  
Potential Source ◽  
Additional Support ◽  
Signaling Interactions ◽  
Heterogeneity Of Cell Populations

Tendon is a dense connective tissue that stores and transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, yet little is known about the diversity of cell types that populate tendon. To address this, we determined the heterogeneity of cell populations within mouse Achilles tendons using single-cell RNA sequencing. In assembling a transcriptomic atlas of Achilles tendons, we identified 11 distinct types of cells, including three previously undescribed populations of tendon fibroblasts. Prior studies have indicated that pericytes, which are found in the vasculature of tendons, could serve as a potential source of progenitor cells for adult tendon fibroblasts. Using trajectory inference analysis, we provide additional support for the notion that pericytes are likely to be at least one of the progenitor cell populations for the fibroblasts that compose adult tendons. We also modeled cell-cell interactions and identified previously undescribed ligand-receptor signaling interactions involved in tendon homeostasis. Our novel and interactive tendon atlas highlights previously underappreciated heterogeneity between and within tendon cell populations. The atlas also serves as a resource to further the understanding of tendon extracellular matrix assembly and maintenance and in the design of therapies for tendinopathies.

scholarly journals Ureter single-cell and spatial mapping reveal cell types, architecture, and signaling networks

2021 ◽  
Author(s):  
Angela H. Ting ◽  
Emily E Fink ◽  
Surbhi Sona ◽  
Uyen Tran ◽  
Pierre-Emmanuel Desprez ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Single Cell ◽  
Communication Networks ◽  
Adult Stem Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Basal Cells ◽  
Human Ureter

Tissue engineering offers a promising treatment strategy for ureteral strictures, but its success requires an in-depth understanding of the architecture, cellular heterogeneity, and signaling pathways underlying tissue regeneration. Here we define and spatially map cell populations within the human ureter using single-cell RNA sequencing, spatial gene expression, and immunofluorescence approaches. We focused on the stromal and urothelial cell populations to enumerate distinct cell types composing the human ureter and inferred potential cell-cell communication networks underpinning the bi-directional crosstalk between these compartments. Furthermore, we analyzed and experimentally validated the importance of Sonic Hedgehog (SHH) signaling pathway in adult stem cell maintenance. The SHH-expressing basal cells supported organoid generation in vitro and accurately predicted the differentiation trajectory from basal stem cells to terminally differentiated umbrella cells. Our results highlight essential processes involved in adult ureter tissue homeostasis and provide a blueprint for guiding ureter tissue engineering.

Molecular and Cellular Dynamics of Aortic Aneurysms Revealed by Single-Cell Transcriptomics

2021 ◽  
Author(s):  
Yanming Li ◽  
Scott A. LeMaire ◽  
Ying H. Shen
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Cell Types ◽  
Cellular Level ◽  
Aortic Aneurysms ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Sequencing Analysis ◽  
Molecular Features ◽  
Single Cell Rna Sequencing

The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases.

scholarly journals Single-cell transcriptomic analysis of mIHC images via antigen mapping

2021 ◽  
Vol 7 (10) ◽  
pp. eabc5464
Author(s):  
Kiya W. Govek ◽  
Emma C. Troisi ◽  
Zhen Miao ◽  
Rachael G. Aubin ◽  
Steven Woodhouse ◽  
...  
Keyword(s):  
Single Cell ◽  
Spatial Patterns ◽  
Cell Types ◽  
Level Of Detail ◽  
Cell Populations ◽  
Sequencing Data ◽  
Spatially Resolved ◽  
Murine Spleen ◽  
Single Cell Rna Sequencing ◽  
Antibody Panel

Highly multiplexed immunohistochemistry (mIHC) enables the staining and quantification of dozens of antigens in a tissue section with single-cell resolution. However, annotating cell populations that differ little in the profiled antigens or for which the antibody panel does not include specific markers is challenging. To overcome this obstacle, we have developed an approach for enriching mIHC images with single-cell RNA sequencing data, building upon recent experimental procedures for augmenting single-cell transcriptomes with concurrent antigen measurements. Spatially-resolved Transcriptomics via Epitope Anchoring (STvEA) performs transcriptome-guided annotation of highly multiplexed cytometry datasets. It increases the level of detail in histological analyses by enabling the systematic annotation of nuanced cell populations, spatial patterns of transcription, and interactions between cell types. We demonstrate the utility of STvEA by uncovering the architecture of poorly characterized cell types in the murine spleen using published cytometry and mIHC data of this organ.

scholarly journals Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bas Molenaar ◽  
Louk T. Timmer ◽  
Marjolein Droog ◽  
Ilaria Perini ◽  
Danielle Versteeg ◽  
...  
Keyword(s):  
Single Cell ◽  
Communication Networks ◽  
Cardiac Remodeling ◽  
Cardiac Injury ◽  
Ischemic Injury ◽  
Cell Types ◽  
Repair Process ◽  
Cardiac Repair ◽  
Cellular Heterogeneity ◽  
Intercellular Signaling

AbstractThe efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair.

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