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Species: mouse
Number of cells: 52019
Study size: 473MB

Liver fibrosis 
Hepatic stellate cells 
Myofibroblasts 

Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis (In vivo)

Oliver Krenkel, Jana Hundertmark, Thomas P. Ritz, Ralf Weiskirchen, Frank Tacke

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis.

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Species: mouse
Number of cells: 8547
Study size: 214MB

Liver fibrosis 
Hepatic stellate cells 
Myofibroblasts 
invitro 

Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis (In vitro)

Oliver Krenkel, Jana Hundertmark, Thomas P. Ritz, Ralf Weiskirchen, Frank Tacke

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis.

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Species: human
Number of cells: 35685
Study size: 977MB

Skin 
mature dendritic cells 
atopic dermatitis 
IL-4R alpha blockade 

Persistence of mature dendritic cells, TH2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4R alpha blockade

Christine Bangert, Katharina Rindler, Thomas Krausgruber, Natalia Alkon, Felix M. Thaler, Harald Kurz, Tanya Ayub, Denis Demirtas, Nikolaus Fortelny, Vera Vorstandlechner, Wolfgang M. Bauer, Tamara Quint, Michael Mildner, Constanze Jonak, Adelheid Elbe-Bürger, Johannes Griss, Christoph Bock, Patrick M. Brunner

Therapeutic options for autoimmune diseases typically consist of broad and targeted immunosuppressive agents. However, sustained clinical benefit is rarely achieved, as the disease phenotype usually returns after cessation of treatment. To better understand tissue-resident immune memory in human disease, we investigated patients with atopic dermatitis (AD) who underwent short-term or long-term treatment with the IL-4R alpha blocker dupilumab. Using multi-omics profiling with single-cell RNA sequencing and multiplex proteomics, we found significant decreases in overall skin immune cell counts and normalization of transcriptomic dysregulation in keratinocytes consistent with clearance of disease. However, we identified specific immune cell populations that persisted for up to a year after clinical remission while being absent from healthy controls. These populations included LAMP3+ CCL22+ mature dendritic cells, CRTH2+ CD161+ T helper (“TH2A”) cells, and CRTAM+ cytotoxic T cells, which expressed high levels of CCL17 (dendritic cells) and IL13 (T cells). TH2A cells showed a characteristic cytokine receptor constellation with IL17RB, IL1RL1 (ST2), and CRLF2 expression, suggesting that these cells are key responders to the AD-typical epidermal alarmins IL-25, IL-33, and TSLP, respectively. We thus identified disease-linked immune cell populations in resolved AD indicative of a persisting disease memory, facilitating a rapid response system of epidermal-dermal cross-talk between keratinocytes, dendritic cells, and T cells. This observation may help to explain the disease recurrence upon termination of immunosuppressive treatments in AD, and it identifies potential disease memory–linked cell types that may be targeted to achieve a more sustained therapeutic response.

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Species: human
Number of cells: 78886
Study size: 2GB

Major depressive disorder 
brain 

Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons

Corina Nagy, Malosree Maitra, Arnaud Tanti, Matthew Suderman, Jean-Francois Théroux, Maria Antonietta Davoli, Kelly Perlman, Volodymyr Yerko, Yu Chang Wang, Shreejoy J. Tripathy, Paul Pavlidis, Naguib Mechawar, Jiannis Ragoussis, Gustavo Turecki

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.

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Species: human
Number of cells: 7269
Study size: 159MB

Immunology 
Resistance 
Skin 
Atopic dermatitis (AD) 
Spontaneously resolved atopic dermatitis 

Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin (Healthy control versus spontaneously healed atopic dermatitis)

Rindler K, Krausgruber T, Thaler FM, Alkon N, Bangert C, Kurz H, Fortelny N, Rojahn TB, Jonak C, Griss J, Bock C, Brunner PM

Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.

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Species: human
Number of cells: 14443
Study size: 340MB

Immunology 
Skin 
Atopic dermatitis (AD) 

Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin (Spontaneously healed atopic dermatitis versus active atopic dermatitis)

Rindler K, Krausgruber T, Thaler FM, Alkon N, Bangert C, Kurz H, Fortelny N, Rojahn TB, Jonak C, Griss J, Bock C, Brunner PM

Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.

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Species: human
Number of cells: 7304
Study size: 562MB

Skin 
psoriatic skin 
CD8+ T cell 

Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8 + T cells in autoimmunity and cancer

Jared Liu, PhD, Hsin-Wen Chang, PhD, Zhi-Ming Huang, PhD, Mio Nakamura, MD, Sahil Sekhon, MD, Richard Ahn, PhD, Priscila Munoz-Sandoval, BA, ShrishtiBhattarai, MS, Kristen M. Beck, MD, Isabelle M. Sanchez, MD, Eric Yang, MD, Mariela Pauli, MS, Sarah T. Arron, MD, PhD, Wai-Ping Fung-Leung, PhD, ErnestoMunoz, PhD, Xuejun Liu, PhD, Tina Bhutani, MD, MAS, Jeffrey North, MD, Anne M.Fourie, PhD, Michael D. Rosenblum, MD, PhD, Wilson Liao, MD

Background: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8+ T cells have been identified as pathogenic drivers. Objective: Our study focused on comprehensively characterizing the phenotypic variation of CD8+ T cells in psoriatic lesions. Methods: We used single-cell RNA-seq to compare CD8+ T cell transcriptomic heterogeneity between psoriatic and healthy skin. Results: We identified 11 transcriptionally diverse CD8+ T cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed two Tc17 subsets that were metabolically divergent, developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high co-inhibitory receptor expression in the Tc17 clusters, a comparison of these cells with melanoma-infiltrating CD8+ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program. Conclusion: Using high resolution single cell profiling in tissue, we have uncovered the diverse landscape of CD8+ T cells in psoriatic and healthy skin, including two non-exhausted Tc17 subsets associated with disease severity.

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Species: mouse
Number of cells: 10070
Study size: 184MB

Cancer 
B cell subset 
Chemotherapy 
Breast 

Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity (Mouse)

Lu, Yiwen and Zhao, Qiyi and Liao, Jian-You and Song, Erwei and Xia, Qidong and Pan, Jiayao and Li, Yihong and Li, Jiaqian and Zhou, Boxuan and Ye, Yingying and others

Understanding molecular mechanisms that dictate B cell diversity is important for targeting B cells as anti-cancer treatment. Through the single-cell dissection of B cell heterogeneity in longitudinal samples of patients with breast cancer before and after neoadjuvant chemotherapy, we revealed that an ICOSL + B cell subset emerges after chemotherapy. Using three immunocompetent mouse models, we recapitulated the subset switch of human tumor-infiltrating B cells during chemotherapy. By employing B-cell-specific deletion mice, we showed that ICOSL in B cells boosts anti-tumor immunity by enhancing the effector to regulatory T cell ratio. The signature of ICOSL + B cells is imprinted by complement-CR2 signaling, which is triggered by immunogenic cell death. Moreover, we identified that CD55, a complement inhibitory protein, determines the opposite roles of B cells in chemotherapy. Collectively, we demonstrated a critical role of the B cell subset switch in chemotherapy response, which has implications in designing novel anti-cancer therapies.

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Species: m_fascicularis
Number of cells: 19297
Study size: 389MB

retina 
peripheral retina 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (peripheral non-neuronal cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 16971
Study size: 298MB

retina 
fovea 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (foveal non-neuronal cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 11723
Study size: 769MB

retina 
peripheral retina 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (peripheral retinal ganglion cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 30297
Study size: 2GB

retina 
fovea 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (foveal retinal ganglion cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 24180
Study size: 800MB

retina 
peripheral retina 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (peripheral amacrine cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 6056
Study size: 145MB

retina 
fovea 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (foveal amacrine cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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Species: m_fascicularis
Number of cells: 9285
Study size: 151MB

retina 
peripheral retina 
primate 

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina (peripheral bipolar cell)

Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S. Bryman, Tavé van Zyl, Michael Tri. H. Do, Aviv Regev, Joshua R. Sanes

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

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