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Article ; Online: Building a high-quality Human Cell Atlas.

Rozenblatt-Rosen, Orit / Shin, Jay W / Rood, Jennifer E / Hupalowska, Anna / Regev, Aviv / Heyn, Holger

2021 Volume 39, Issue 2, Page(s) 149–153

MeSH term(s)	Benchmarking ; Cells/cytology ; Cost-Benefit Analysis ; Decision Trees ; Humans ; Reproducibility of Results
Language	English
Publishing date	2021-01-26
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-020-00812-4
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission.

Ding, Jiarui / Garber, John J / Uchida, Amiko / Lefkovith, Ariel / Carter, Grace T / Vimalathas, Praveen / Canha, Lauren / Dougan, Michael / Staller, Kyle / Yarze, Joseph / Delorey, Toni M / Rozenblatt-Rosen, Orit / Ashenberg, Orr / Graham, Daniel B / Deguine, Jacques / Regev, Aviv / Xavier, Ramnik J

Nature communications

2024 Volume 15, Issue 1, Page(s) 3344

Abstract: Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the ... ...

Abstract	Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15
MeSH term(s)	Humans ; Eosinophilic Esophagitis/genetics ; Eosinophilic Esophagitis/pathology ; Endothelial Cells/metabolism ; Interleukin-13 ; Inflammation/genetics
Chemical Substances	Interleukin-13
Language	English
Publishing date	2024-04-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47647-0
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Article ; Online: TACCO unifies annotation transfer and decomposition of cell identities for single-cell and spatial omics.

Mages, Simon / Moriel, Noa / Avraham-Davidi, Inbal / Murray, Evan / Watter, Jan / Chen, Fei / Rozenblatt-Rosen, Orit / Klughammer, Johanna / Regev, Aviv / Nitzan, Mor

Nature biotechnology

2023 Volume 41, Issue 10, Page(s) 1465–1473

Abstract: Transferring annotations of single-cell-, spatial- and multi-omics data is often challenging owing both to technical limitations, such as low spatial resolution or high dropout fraction, and to biological variations, such as continuous spectra of cell ... ...

Abstract	Transferring annotations of single-cell-, spatial- and multi-omics data is often challenging owing both to technical limitations, such as low spatial resolution or high dropout fraction, and to biological variations, such as continuous spectra of cell states. Based on the concept that these data are often best described as continuous mixtures of cells or molecules, we present a computational framework for the transfer of annotations to cells and their combinations (TACCO), which consists of an optimal transport model extended with different wrappers to annotate a wide variety of data. We apply TACCO to identify cell types and states, decipher spatiomolecular tissue structure at the cell and molecular level and resolve differentiation trajectories using synthetic and biological datasets. While matching or exceeding the accuracy of specialized tools for the individual tasks, TACCO reduces the computational requirements by up to an order of magnitude and scales to larger datasets (for example, considering the runtime of annotation transfer for 1 M simulated dropout observations).
MeSH term(s)	Multiomics ; Single-Cell Analysis ; Data Curation
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-023-01657-3
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Article: A cellular and spatial atlas of

bioRxiv : the preprint server for biology

2024

Abstract: ... ...

Abstract	TP53
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.28.546977
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Article ; Online: Multicellular communities are perturbed in the aging human brain and Alzheimer's disease.

Cain, Anael / Taga, Mariko / McCabe, Cristin / Green, Gilad S / Hekselman, Idan / White, Charles C / Lee, Dylan I / Gaur, Pallavi / Rozenblatt-Rosen, Orit / Zhang, Feng / Yeger-Lotem, Esti / Bennett, David A / Yang, Hyun-Sik / Regev, Aviv / Menon, Vilas / Habib, Naomi / De Jager, Philip L

Nature neuroscience

2023 Volume 26, Issue 7, Page(s) 1267–1280

Abstract: The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA ... ...

Abstract	The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Endothelial Cells/metabolism ; Brain/metabolism ; Aging/pathology ; Cognitive Dysfunction/pathology ; Neocortex/pathology
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-023-01356-x
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function.

Tang, Ruihan / Acharya, Nandini / Subramanian, Ayshwarya / Purohit, Vinee / Tabaka, Marcin / Hou, Yu / He, Danyang / Dixon, Karen O / Lambden, Connor / Xia, Junrong / Rozenblatt-Rosen, Orit / Sobel, Raymond A / Wang, Chao / Regev, Aviv / Anderson, Ana C / Kuchroo, Vijay K

Science immunology

2022 Volume 7, Issue 69, Page(s) eabm0631

Abstract: Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of ... ...

Abstract	Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer. Bat3 is an adaptor protein that binds to the tail of Tim-3; therefore, we studied its role in regulating the functional status of DCs. In murine models of autoimmunity (experimental autoimmune encephalomyelitis) and cancer (MC38-OVA-implanted tumor), lack of Bat3 expression in DCs alters the T cell compartment-it decreases T
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Autoimmunity ; Dendritic Cells ; Encephalomyelitis, Autoimmune, Experimental ; Hepatitis A Virus Cellular Receptor 2 ; Mice ; Molecular Chaperones/metabolism ; Nuclear Proteins/metabolism ; T-Lymphocytes, Regulatory
Chemical Substances	Adaptor Proteins, Signal Transducing ; Bag6 protein, mouse ; Hepatitis A Virus Cellular Receptor 2 ; Molecular Chaperones ; Nuclear Proteins
Language	English
Publishing date	2022-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abm0631
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Article ; Online: Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing.

Simmons, Sean K / Lithwick-Yanai, Gila / Adiconis, Xian / Oberstrass, Florian / Iremadze, Nika / Geiger-Schuller, Kathryn / Thakore, Pratiksha I / Frangieh, Chris J / Barad, Omer / Almogy, Gilad / Rozenblatt-Rosen, Orit / Regev, Aviv / Lipson, Doron / Levin, Joshua Z

Nature biotechnology

2022 Volume 41, Issue 2, Page(s) 204–211

Abstract: Here we introduce a mostly natural sequencing-by-synthesis (mnSBS) method for single-cell RNA sequencing (scRNA-seq), adapted to the Ultima genomics platform, and systematically benchmark it against current scRNA-seq technology. mnSBS uses mostly natural, ...

Abstract	Here we introduce a mostly natural sequencing-by-synthesis (mnSBS) method for single-cell RNA sequencing (scRNA-seq), adapted to the Ultima genomics platform, and systematically benchmark it against current scRNA-seq technology. mnSBS uses mostly natural, unmodified nucleotides and only a low fraction of fluorescently labeled nucleotides, which allows for high polymerase processivity and lower costs. We demonstrate successful application in four scRNA-seq case studies of different technical and biological types, including 5' and 3' scRNA-seq, human peripheral blood mononuclear cells from a single individual and in multiplex, as well as Perturb-Seq. Benchmarking shows that results from mnSBS-based scRNA-seq are very similar to those using Illumina sequencing, with minor differences in results related to the position of reads relative to annotated gene boundaries, owing to single-end reads of Ultima being closer to gene ends than reads from Illumina. The method is thus compatible with state-of-the-art scRNA-seq libraries independent of the sequencing technology. We expect mnSBS to be of particular utility for cost-effective large-scale scRNA-seq projects.
MeSH term(s)	Humans ; Gene Expression Profiling/methods ; Sequence Analysis, RNA/methods ; Leukocytes, Mononuclear ; Single-Cell Gene Expression Analysis ; Single-Cell Analysis/methods ; Nucleotides
Chemical Substances	Nucleotides
Language	English
Publishing date	2022-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-022-01452-6
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

Fujita, Masashi / Gao, Zongmei / Zeng, Lu / McCabe, Cristin / White, Charles C / Ng, Bernard / Green, Gilad Sahar / Rozenblatt-Rosen, Orit / Phillips, Devan / Amir-Zilberstein, Liat / Lee, Hyo / Pearse, Richard V / Khan, Atlas / Vardarajan, Badri N / Kiryluk, Krzysztof / Ye, Chun Jimmie / Klein, Hans-Ulrich / Wang, Gao / Regev, Aviv /

Habib, Naomi / Schneider, Julie A / Wang, Yanling / Young-Pearse, Tracy / Mostafavi, Sara / Bennett, David A / Menon, Vilas / De Jager, Philip L

Nature genetics

2024 Volume 56, Issue 4, Page(s) 605–614

Abstract: The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of ... ...

Abstract	The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Genome-Wide Association Study/methods ; Brain/metabolism ; Quantitative Trait Loci/genetics ; Genetic Variation/genetics ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics
Chemical Substances	TMEM106B protein, human ; Membrane Proteins ; Nerve Tissue Proteins
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-024-01685-y
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium.

bioRxiv : the preprint server for biology

2023

Abstract: The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma- ... ...

Abstract	The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendants
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.28.569028
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Article: Inference of single cell profiles from histology stains with the Single-Cell omics from Histology Analysis Framework (SCHAF).

Comiter, Charles / Vaishnav, Eeshit Dhaval / Ciampricotti, Metamia / Li, Bo / Yang, Yiming / Rodig, Scott J / Turner, Madison / Pfaff, Kathleen L / Jané-Valbuena, Judit / Slyper, Michal / Waldman, Julia / Vigneau, Sebastian / Wu, Jingyi / Blosser, Timothy R / Segerstolpe, Åsa / Abravanel, Daniel / Wagle, Nikil / Zhuang, Xiaowei / Rudin, Charles M /

Klughammer, Johanna / Rozenblatt-Rosen, Orit / Kobayash-Kirschvink, Koseki J / Shu, Jian / Regev, Aviv

bioRxiv : the preprint server for biology

2023

Abstract: Tissue biology involves an intricate balance between cell-intrinsic processes and interactions between cells organized in specific spatial patterns, which can be respectively captured by single-cell profiling methods, such as single-cell RNA-seq (scRNA- ... ...

Abstract	Tissue biology involves an intricate balance between cell-intrinsic processes and interactions between cells organized in specific spatial patterns, which can be respectively captured by single-cell profiling methods, such as single-cell RNA-seq (scRNA-seq), and histology imaging data, such as Hematoxylin-and-Eosin (H&E) stains. While single-cell profiles provide rich molecular information, they can be challenging to collect routinely and do not have spatial resolution. Conversely, histological H&E assays have been a cornerstone of tissue pathology for decades, but do not directly report on molecular details, although the observed structure they capture arises from molecules and cells. Here, we leverage adversarial machine learning to develop SCHAF (Single-Cell omics from Histology Analysis Framework), to generate a tissue sample's spatially-resolved single-cell omics dataset from its H&E histology image. We demonstrate SCHAF on two types of human tumors-from lung and metastatic breast cancer-training with matched samples analyzed by both sc/snRNA-seq and by H&E staining. SCHAF generated appropriate single-cell profiles from histology images in test data, related them spatially, and compared well to ground-truth scRNA-Seq, expert pathologist annotations, or direct MERFISH measurements. SCHAF opens the way to next-generation H&E2.0 analyses and an integrated understanding of cell and tissue biology in health and disease.
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.21.533680
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