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Species: human
Number of cells: 32915
Number of downloads: 6
Study size: 1GB
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immuno-oncology 
Cancer 
Kidney 
Clear cell renal carcinoma 

Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages (Hematopoietic - VIPER-based clustering)

Aleksandar Obradovic, Nivedita Chowdhury, Scott M. Haake, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V. Guo, David H. Aggen, W. Kimryn Rathmell, Eric Jonasch, Joyce E. Johnson, Marc Roth, Kathryn E. Beckermann, Brian I. Rini, James McKiernan, Andrea Califano, and Charles G. Drake

Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. Keywords: kidney, renal, cancer, tumor

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Species: human
Number of cells: 102385
Number of downloads: 2
Study size: 2GB
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Immunology 
Oncology 
Kidney 
Clear cell renal carcinoma 

Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages (Hematopoietic - Gene expression)

Aleksandar Obradovic, Nivedita Chowdhury, Scott M Haake, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V Guo, David H Aggen, W Kimryn Rathmell, Eric Jonasch, Joyce E Johnson, Marc Roth, Kathryn E Beckermann, Brian I Rini, James McKiernan, Andrea Califano, Charles G Drake

Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. Keywords: kidney, renal, cancer, tumor

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Species: human
Number of cells: 19781
Number of downloads: 2
Study size: 472MB
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immuno-oncology 
Cancer 
Kidney 
Clear cell renal carcinoma 

Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages (Non-hematopoietic - VIPER-based clustering)

Aleksandar Obradovic, Nivedita Chowdhury, Scott M. Haake, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V. Guo, David H. Aggen, W. Kimryn Rathmell, Eric Jonasch, Joyce E. Johnson, Marc Roth, Kathryn E. Beckermann, Brian I. Rini, James McKiernan, Andrea Califano, and Charles G. Drake

Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. Keywords: kidney, renal, cancer, tumor

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Species: human
Number of cells: 61583
Number of downloads: 1
Study size: 2GB
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Immunology 
Oncology 
Kidney 
Clear cell renal carcinoma 

Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages (Non-hematopoietic - Gene expression)

Aleksandar Obradovic, Nivedita Chowdhury, Scott M Haake, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V Guo, David H Aggen, W Kimryn Rathmell, Eric Jonasch, Joyce E Johnson, Marc Roth, Kathryn E Beckermann, Brian I Rini, James McKiernan, Andrea Califano, Charles G Drake

Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. Keywords: kidney, renal, cancer, tumor

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Species: human
Number of cells: 68637
Number of downloads: 2
Study size: 1GB
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Kidney 
autosomal dominant polycystic kidney disease 

Heterogeneity of cell composition and origin identified by single-cell transcriptomics in renal cysts of patients with autosomal dominant polycystic kidney disease

Qiong Li, Yuchen Wang, Wenfeng Deng, Yanna Liu, Jian Geng, Ziyan Yan, Fei Li, Binshen Chen, Zhuolin Li, Renfei Xia, Wenli Zeng, Rumin Liu, Jian Xu, Fu Xiong, Chin-Lee Wu, and Yun Miao

Rationale: Renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD) can originate from any nephron segments, including proximal tubules (PT), the loop of Henle (LOH), distal tubules (DT), and collecting ducts (CD). Previous studies mostly used limited cell markers and failed to identify cells negative for these markers. Therefore, the cell composition and origin of ADPKD cyst are still unclear, and mechanisms of cystogenesis of different origins await further exploration. Methods: We performed single-cell RNA sequencing for the normal kidney tissue and seven cysts derived from superficial or deep layers of the polycystic kidney from an ADPKD patient. Results: Twelve cell types were identified and analyzed. We found that a renal cyst could be derived either from CD or both PT and LOH. Gene set variation analysis (GSVA) showed that epithelial mesenchymal transition (EMT), TNFA signaling via the NFKB pathways, and xenobiotic metabolism were significantly activated in PT-derived cyst epithelial cells while robust expression of genes involved in G2M Checkpoint, mTORC1 signaling, E2F Targets, MYC Targets V1, MYC Targets V2 were observed in CD-derived cells. Conclusion: Our results revealed that a single cyst could originate from CD or both PT and LOH, suggesting heterogeneity of polycystic composition and origin. Furthermore, cyst epithelial cells with different origins have different gene set activation.

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Species: human
Number of cells: 489490
Number of downloads: 13
Study size: 7GB
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Immunology 
Oncology 
Breast 
Triple-negative breast cancer 

Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer

Yuanyuan Zhang, Hongyan Chen, Hongnan Mo, Xueda Hu, Ranran Gao, Yahui Zhao, Baolin Liu, Lijuan Niu, Xiaoying Sun, Xiao Yu, Yong Wang, Qing Chang, Tongyang Gong, Xiuwen Guan, Ting Hu, Tianyi Qian, Binghe Xu, Fei Ma, Zemin Zhang, Zhihua Liu

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.

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Species: human
Number of cells: 7165
Number of downloads: 18
Study size: 150MB
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Multiple myeloma 
Bone marrow 
Natural killer cell 
Adaptive NK cell 
Daratumumab 

Adaptive Natural Killer Cells Facilitate Effector Functions of Daratumumab in Multiple Myeloma

Hyunsoo Cho, Kyung Hwan Kim, Hoyoung Lee, Chang Gon Kim, Haerim Chung, Yoon Seok Choi, Su-Hyung Park, June-Won Cheong, Yoo Hong Min, Eui-Cheol Shin, Jin Seok Kim

Purpose: To investigate the different roles of heterogeneous natural killer (NK)-cell subpopulations in multiple myeloma and to identify NK-cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC). Experimental design: We performed single-cell RNA sequencing of NK cells from patients with newly diagnosed multiple myeloma (NDMM) and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 patients with NDMM. Results: Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in patients with NDMM. Unlike conventional NK cells, sorted adaptive NK cells from the BM of patients with NDMM exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Conclusions: Our findings indicate that adaptive NK cells are an important mediator of ADCC in multiple myeloma and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.

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Species: human
Number of cells: 183913
Number of downloads: 57
Study size: 4GB
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Immunology 
immuno-oncology 
pan-cancer 

Pan-cancer single-cell landscape of tumor-infiltrating T cells (10X)

LIANGTAO ZHENG, SHISHANG QIN, WEN SI, ANQIANG WANG, BAOCAI XING, RANRAN GAO, XIANWEN REN, LI WANG, XIAOJIANG WU, JI ZHANG, NAN WU, NING ZHANG, HONG ZHENG, HANQIANG OUYANG, KEYUAN CHEN, ZHAODE BU, XUEDA HU, JIAFU JI, AND ZEMIN ZHANG

T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8+ T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.

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Species: human
Number of cells: 542
Number of downloads: 37
Study size: 26MB
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Immunology 
immuno-oncology 
pan-cancer 

Pan-cancer single-cell landscape of tumor-infiltrating T cells (smart-seq2)

LIANGTAO ZHENG, SHISHANG QIN, WEN SI, ANQIANG WANG, BAOCAI XING, RANRAN GAO, XIANWEN REN, LI WANG, XIAOJIANG WU, JI ZHANG, NAN WU, NING ZHANG, HONG ZHENG, HANQIANG OUYANG, KEYUAN CHEN, ZHAODE BU, XUEDA HU, JIAFU JI, AND ZEMIN ZHANG

T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8+ T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.

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Species: human
Number of cells: 72887
Number of downloads: 13
Study size: 3GB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Combined)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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Species: human
Number of cells: 15177
Number of downloads: 8
Study size: 648MB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Amygdala)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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Species: human
Number of cells: 11202
Number of downloads: 3
Study size: 545MB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Dorsolateral prefrontal cortex)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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Species: human
Number of cells: 10268
Number of downloads: 3
Study size: 386MB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Hippocampus)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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Species: human
Number of cells: 20571
Number of downloads: 3
Study size: 1GB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Nucleus accumbens)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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Species: human
Number of cells: 15669
Number of downloads: 1
Study size: 868MB
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Human Cell Atlas 
Brain 

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain (Subgenual anterior cingulate cortex)

Matthew N. Tran, Kristen R. Maynard, Abby Spangler, Louise A. Huuki, Kelsey D. Montgomery, Vijay Sadashivaiah, Madhavi Tippani, Brianna K. Barry, Dana B. Hancock, Stephanie C. Hicks, Joel E. Kleinman, Thomas M. Hyde, Leonardo Collado-Torres, Andrew E. Jaffe, Keri Martinowich

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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