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3 results on '"Haber, Adam L."'

1. T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Author

Biton, Moshe, Haber, Adam L, Rogel, Noga, Burgin, Grace, Beyaz, Semir, Schnell, Alexandra, Ashenberg, Orr, Su, Chien-Wen, Smillie, Christopher, Shekhar, Karthik, Chen, Zuojia, Wu, Chuan, Ordovas-Montanes, Jose, Alvarez, David, Herbst, Rebecca H, Zhang, Mei, Tirosh, Itay, Dionne, Danielle, Nguyen, Lan T, Xifaras, Michael E, Shalek, Alex K, von Andrian, Ulrich H, Graham, Daniel B, Rozenblatt-Rosen, Orit, Shi, Hai Ning, Kuchroo, Vijay, Yilmaz, Omer H, Regev, Aviv, and Xavier, Ramnik J

Subjects
Biodefense, Digestive Diseases, Regenerative Medicine, Stem Cell Research, Prevention, Vaccine Related, Stem Cell Research - Nonembryonic - Non-Human, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Animals, Cell Differentiation, Cell Self Renewal, Cytokines, Epithelial Cells, Female, Histocompatibility Antigens Class II, Immune System, Interleukin-10, Intestines, Male, Mice, Mice, Inbred C57BL, Organoids, Receptors, G-Protein-Coupled, Salmonella enterica, Stem Cells, T-Lymphocytes, Helper-Inducer, ISCs, MHC class II, MHCII, T helper, T regulatory, T(reg), Th, epithelial differentiation, gut biology, intestinal stem cells, mucosal immunity, scRNA-seq, single cell RNA-seq, stem cell renewal, tuft cells, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.

Published
2018

2. A single-cell survey of the small intestinal epithelium

Author

Haber, Adam L, Biton, Moshe, Rogel, Noga, Herbst, Rebecca H, Shekhar, Karthik, Smillie, Christopher, Burgin, Grace, Delorey, Toni M, Howitt, Michael R, Katz, Yarden, Tirosh, Itay, Beyaz, Semir, Dionne, Danielle, Zhang, Mei, Raychowdhury, Raktima, Garrett, Wendy S, Rozenblatt-Rosen, Orit, Shi, Hai Ning, Yilmaz, Omer, Xavier, Ramnik J, and Regev, Aviv

Subjects
Emerging Infectious Diseases, Digestive Diseases, Infectious Diseases, Vaccine Related, Aetiology, 2.1 Biological and endogenous factors, Animals, Cell Differentiation, Cytokines, Enterocytes, Epithelial Cells, Epithelium, Female, Gene Expression Profiling, Homeostasis, Intestine, Small, Leukocyte Common Antigens, Male, Mice, Organoids, Paneth Cells, Single-Cell Analysis, Transcription, Genetic, Thymic Stromal Lymphopoietin, General Science & Technology
Abstract

Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells. We also characterized the ways in which cell-intrinsic states and the proportions of different cell types respond to bacterial and helminth infections: Salmonella infection caused an increase in the abundance of Paneth cells and enterocytes, and broad activation of an antimicrobial program; Heligmosomoides polygyrus caused an increase in the abundance of goblet and tuft cells. Our survey highlights previously unidentified markers and programs, associates sensory molecules with cell types, and uncovers principles of gut homeostasis and response to pathogens.

Published
2017

3. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Author

Christoph, Muus, Luecken , Malte D., Gökcen, Eraslan, Lisa, Sikkema, Avinash, Waghray, Graham, Heimberg, Yoshihiko, Kobayashi, Eeshit Dhaval Vaishnav, Ayshwarya, Subramanian, Christopher, Smillie, Jagadeesh, Karthik A., Elizabeth Thu Duong, Evgenij, Fiskin, Elena Torlai Triglia, Meshal, Ansari, Peiwen, Cai, Brian, Lin, Justin, Buchanan, Sijia, Chen, Jian, Shu, Haber, Adam L., Hattie, Chung, Montoro, Daniel T., Taylor, Adams, Hananeh, Aliee, Allon, Samuel J., Zaneta, Andrusivova, Ilias, Angelidis, Orr, Ashenberg, Kevin, Bassler, Christophe, Bécavin, Inbal, Benhar, Joseph, Bergenstråhle, Ludvig, Bergenstråhle, Liam, Bolt, Emelie, Braun, Bui, Linh T., Steven, Callori, Mark, Chaffin, Evgeny, Chichelnitskiy, Joshua, Chiou, Conlon, Thomas M., Cuoco, Michael S., Cuomo, Anna S. E., Marie, Deprez, Grant, Duclos, Denise, Fine, Fischer, David S., Shila, Ghazanfar, Astrid, Gillich, Bruno, Giotti, Joshua, Gould, Minzhe, Guo, Gutierrez, Austin J., Habermann, Arun C., Tyler, Harvey, Peng, He, Xiaomeng, Hou, Lijuan, Hu, Yan, Hu, Alok, Jaiswal, Lu, Ji, Peiyong, Jiang, Kapellos, Theodoros S., Kuo, Christin S., Ludvig, Larsson, Leney-Greene, Michael A., Kyungtae, Lim, Monika, Litviňuková, Ludwig, Leif S., Soeren, Lukassen, Wendy, Luo, Henrike, Maatz, Elo, Madissoon, Lira, Mamanova, Kasidet, Manakongtreecheep, Sylvie, Leroy, Mayr, Christoph H., Mbano, Ian M., Mcadams, Alexi M., Nabhan, Ahmad N., Nyquist, Sarah K., Lolita, Penland, Poirion, Olivier B., Sergio, Poli, Cancan, Qi, Rachel, Queen, Daniel, Reichart, Ivan, Rosas, Schupp, Jonas C., Shea, Conor V., Xingyi, Shi, Rahul, Sinha, Sit, Rene V., Kamil, Slowikowski, Michal, Slyper, Smith, Neal P., Alex, Sountoulidis, Maximilian, Strunz, Sullivan, Travis B., Dawei, Sun, Carlos, Talavera-López, Peng, Tan, Jessica, Tantivit, Travaglini, Kyle J., Tucker, Nathan R., Vernon, Katherine A., Wadsworth, Marc H., Julia, Waldman, Xiuting, Wang, Ke, Xu, Wenjun, Yan, William, Zhao, Ziegler, Carly G. K., The NHLBI LungMap Consortium, Zerti, Darin, The Human Cell Atlas Lung Biological Network, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
0301 basic medicine, Male, Cathepsin L, Respiratory System, Datasets as Topic, Lung/metabolism, Sequence Analysis, RNA/methods, Organ Specificity/genetics, 0302 clinical medicine, 80 and over, Respiratory system, Lung, COVID-19/epidemiology, Aged, 80 and over, Serine Endopeptidases, General Medicine, respiratory system, Middle Aged, Host-Pathogen Interactions/genetics, 3. Good health, Angiotensin-Converting Enzyme 2/genetics, medicine.anatomical_structure, Datasets as Topic/statistics & numerical data, Respiratory System/metabolism, Organ Specificity, Cathepsin L/genetics, 030220 oncology & carcinogenesis, Host-Pathogen Interactions, Tumor necrosis factor alpha, Female, Angiotensin-Converting Enzyme 2, Single-Cell Analysis, RNA/methods, Sequence Analysis, Adult, Alveolar Epithelial Cells/metabolism, Serine Endopeptidases/genetics, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Immune system, Viral entry, Parenchyma, medicine, Humans, Gene Expression Profiling/statistics & numerical data, Aged, Demography, SARS-CoV-2, Sequence Analysis, RNA, Gene Expression Profiling, Single-Cell Analysis/methods, COVID-19, Virus Internalization, Gene expression profiling, 030104 developmental biology, Alveolar Epithelial Cells, Immunology, Tissue tropism, SARS-CoV-2/physiology
Abstract

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

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