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Article ; Online: The protein expression profile of ACE2 in human tissues

Feria Hikmet / Loren Méar / Mathias Uhlén / Cecilia Lindskog

Abstract: ABSTRACTThe international spread of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on both healthcare and society. A multitude of research efforts worldwide aim at characterizing the cellular factors involved in viral ... ...

Abstract	ABSTRACTThe international spread of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on both healthcare and society. A multitude of research efforts worldwide aim at characterizing the cellular factors involved in viral transmission in order to reveal therapeutic targets. For a full understanding of the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is Angiotensin I converting enzyme 2 (ACE2), and its expression has been reported in various human organs, in some cases with inconsistent or contradictory results. Here, we aim to verify a reliable expression profile of ACE2 in all major human tissues and cell types. Based on stringently validated immunohistochemical analysis and high-throughput mRNA sequencing from several datasets, we found that ACE2 expression is mainly localized to microvilli of the intestinal tract and renal proximal tubules, gallbladder epithelium, testicular Sertoli cells and Leydig cells, glandular cells of seminal vesicle and cardiomyocytes. The expression in several other previously reported locations, including alveolar type II (AT2) cells, could not be confirmed. Furthermore, ACE2 expression was absent in the AT2 lung carcinoma cell line A549, often used as a model for viral replication studies. Our analysis suggests that the expression of ACE2 in the human respiratory system appears to be limited, and the expression of the receptor in lung or respiratory epithelia on the protein level is yet to be confirmed. This raises questions regarding the role of ACE2 for infection of human lungs and highlights the need to further explore the route of transmission during SARS-CoV-2 infection.
Keywords	covid19
Publisher	biorxiv
Document type	Article ; Online
DOI	10.1101/2020.03.31.016048
Database	COVID19

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Article ; Online: The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas.

Anna Dénes / Thomas Olsson Bontell / Hanna Barchéus / Sandra Ferreyra Vega / Helena Carén / Cecilia Lindskog / Asgeir S Jakola / Anja Smits

PLoS ONE, Vol 18, Iss 5, p e

2023 Volume 0285732

Abstract: Objectives Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the ... ...

Abstract	Objectives Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. Methods Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. Results In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). Conclusion Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in ...
Keywords	Medicine ; R ; Science ; Q
Subject code	570 ; 616
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The protein expression profile of ACE2 in human tissues

Feria Hikmet / Loren Méar / Åsa Edvinsson / Patrick Micke / Mathias Uhlén / Cecilia Lindskog

Molecular Systems Biology, Vol 16, Iss 7, Pp n/a-n/a (2020)

2020

Abstract: Abstract The novel SARS‐coronavirus 2 (SARS‐CoV‐2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS‐CoV‐2 infection, the cell type‐specific expression of the host cell surface receptor is necessary. The ... ...

Abstract	Abstract The novel SARS‐coronavirus 2 (SARS‐CoV‐2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS‐CoV‐2 infection, the cell type‐specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS‐CoV‐2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.
Keywords	ACE2 ; immunohistochemistry ; respiratory system ; SARS‐CoV-2 ; transcriptomics ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
Subject code	570
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Candidate protein biomarkers in pancreatic neuroendocrine neoplasms grade 3

Abir Salwa Ali / Aurel Perren / Cecilia Lindskog / Staffan Welin / Halfdan Sorbye / Malin Grönberg / Eva Tiensuu Janson

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 9

Abstract: Abstract Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumours that compose 1–2% of all pancreatic tumours. Patients with metastatic grade 3 neoplasia are usually treated with chemotherapy but have a poor progression-free and overall survival. ... ...

Abstract	Abstract Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumours that compose 1–2% of all pancreatic tumours. Patients with metastatic grade 3 neoplasia are usually treated with chemotherapy but have a poor progression-free and overall survival. According to the WHO 2017 classification, they are divided into neuroendocrine tumours (NETs) G3 and neuroendocrine carcinomas (NECs). Despite the new classification, new diagnostic and prognostic biomarkers are needed to sub-categorise the patients and to help guide therapy decisions. Blood from 42 patients and 42 healthy controls were screened for the presence of 92 proteins with the Immuno-Oncology panel using the Proximity Extension Assay provided by Olink Biosciences. Immunohistochemical staining of FAS ligand (FASLG) was performed on 16 patient tumour specimens using a commercial antibody. Fifty-four out of 87 evaluable proteins differed significantly in concentration between blood from patients and blood from healthy controls. FASLG was the only protein for which the concentration in blood was significantly lower in patients compared to controls and the levels correlated negatively to Ki-67 index. Seven of 14 evaluable PanNEN G3 specimens showed FASLG immunoreactivity in the tumour cells while there was scattered immunoreactivity in immune cells. Positive FASLG immunoreactivity correlated to well-differentiated morphology. FASLG concentration in blood was significantly lower in patients with pancreatic NENs G3 compared to controls, and the expression in tumour tissue was variable. Furthermore, FASLG was negatively correlated to Ki-67 and was more frequently expressed in well-differentiated tumours. Taken together, these results may suggest a role of FASLG in PanNENs.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptomics resources of human tissues and organs

Mathias Uhlén / Björn M Hallström / Cecilia Lindskog / Adil Mardinoglu / Fredrik Pontén / Jens Nielsen

Molecular Systems Biology, Vol 12, Iss 4, Pp n/a-n/a (2016)

2016

Abstract: Abstract Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large‐scale transcriptomics studies have analyzed the expression of protein‐ ... ...

Abstract	Abstract Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large‐scale transcriptomics studies have analyzed the expression of protein‐coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue‐restricted manner. Here, we review publicly available human transcriptome resources and discuss body‐wide data from independent genome‐wide transcriptome analyses of different tissues. Gene expression measurements from these independent datasets, generated using samples from fresh frozen surgical specimens and postmortem tissues, are consistent. Overall, the different genome‐wide analyses support a distribution in which many proteins are found in all tissues and relatively few in a tissue‐restricted manner. Moreover, we discuss the applications of publicly available omics data for building genome‐scale metabolic models, used for analyzing cell and tissue functions both in physiological and in disease contexts.
Keywords	genome‐scale metabolic models ; proteomics ; transcriptomics ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2016-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Charting the human proteome: Understanding disease using a tissue-based atlas

UhlÃ©n, Mathias / Cecilia Lindskog / Fredrik PontÃ©n

Science. 2015 Mar. 13, v. 347, no. 6227

2015

Abstract: A decade on from the completion of the Human Genome, the Human Protein Atlas, a multinational research project supported by the non-profit Knut and Alice Wallenberg Foundation, recently launched (November 6, 2014) an open source tissue-based interactive ... ...

Abstract	A decade on from the completion of the Human Genome, the Human Protein Atlas, a multinational research project supported by the non-profit Knut and Alice Wallenberg Foundation, recently launched (November 6, 2014) an open source tissue-based interactive map of the human proteome. A team of multidisciplinary researchers with expertise spanning biotechnology, information technology, and medicine have used a combination of several 'omics technologies to map proteins down to the single cell level, showing both proteins restricted to certain tissuesâsuch as the brain, heart, or liverâand those present in all tissues. It has taken this team over 1,000 person years to compile a searchable, open source database (www.proteinatlas.org) comprising 13 million annotated images of human tissues. The interactive database is aimed at researchers interested in basic research into human biology as well as those working in translational medicine. In this webinar, three of the researchers involved in this program will provide their insights regarding the lessons learned from this intensive effort to map the human proteome. View the Webinar
Keywords	biotechnology ; brain ; databases ; genome ; heart ; humans ; medicine ; proteins ; proteome ; researchers ; tissues ; translation (genetics)
Language	English
Dates of publication	2015-0313
Size	p. 1274.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Genome-wide annotation of protein-coding genes in pig

Max Karlsson / Evelina Sjöstedt / Per Oksvold / Åsa Sivertsson / Jinrong Huang / María Bueno Álvez / Muhammad Arif / Xiangyu Li / Lin Lin / Jiaying Yu / Tao Ma / Fengping Xu / Peng Han / Hui Jiang / Adil Mardinoglu / Cheng Zhang / Kalle von Feilitzen / Xun Xu / Jian Wang /

Huanming Yang / Lars Bolund / Wen Zhong / Linn Fagerberg / Cecilia Lindskog / Fredrik Pontén / Jan Mulder / Yonglun Luo / Mathias Uhlen

BMC Biology, Vol 20, Iss 1, Pp 1-

2022 Volume 18

Abstract: Abstract Background There is a need for functional genome-wide annotation of the protein-coding genes to get a deeper understanding of mammalian biology. Here, a new annotation strategy is introduced based on dimensionality reduction and density-based ... ...

Abstract	Abstract Background There is a need for functional genome-wide annotation of the protein-coding genes to get a deeper understanding of mammalian biology. Here, a new annotation strategy is introduced based on dimensionality reduction and density-based clustering of whole-body co-expression patterns. This strategy has been used to explore the gene expression landscape in pig, and we present a whole-body map of all protein-coding genes in all major pig tissues and organs. Results An open-access pig expression map ( www.rnaatlas.org ) is presented based on the expression of 350 samples across 98 well-defined pig tissues divided into 44 tissue groups. A new UMAP-based classification scheme is introduced, in which all protein-coding genes are stratified into tissue expression clusters based on body-wide expression profiles. The distribution and tissue specificity of all 22,342 protein-coding pig genes are presented. Conclusions Here, we present a new genome-wide annotation strategy based on dimensionality reduction and density-based clustering. A genome-wide resource of the transcriptome map across all major tissues and organs in pig is presented, and the data is available as an open-access resource ( www.rnaatlas.org ), including a comparison to the expression of human orthologs.
Keywords	Annotation ; Protein-coding genes ; Genome-wide ; Transcriptome ; Gene expression ; Tissue expression profile ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The human pancreas proteome defined by transcriptomics and antibody-based profiling.

Angelika Danielsson / Fredrik Pontén / Linn Fagerberg / Björn M Hallström / Jochen M Schwenk / Mathias Uhlén / Olle Korsgren / Cecilia Lindskog

PLoS ONE, Vol 9, Iss 12, p e

2014 Volume 115421

Abstract: The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the ... ...

Abstract	The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhanced validation of antibodies for research applications

Fredrik Edfors / Andreas Hober / Klas Linderbäck / Gianluca Maddalo / Alireza Azimi / Åsa Sivertsson / Hanna Tegel / Sophia Hober / Cristina Al-Khalili Szigyarto / Linn Fagerberg / Kalle von Feilitzen / Per Oksvold / Cecilia Lindskog / Björn Forsström / Mathias Uhlen

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 10

Abstract: Five validation pillars have been proposed to verify the specificity of research antibodies. Here the authors screen 6,000 antibodies from the Human Protein Atlas with these methods to provide an antibody validation resource for providers and users. ...

Abstract	Five validation pillars have been proposed to verify the specificity of research antibodies. Here the authors screen 6,000 antibodies from the Human Protein Atlas with these methods to provide an antibody validation resource for providers and users.
Keywords	Science ; Q
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhanced validation of antibodies for research applications

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 10

Abstract	Five validation pillars have been proposed to verify the specificity of research antibodies. Here the authors screen 6,000 antibodies from the Human Protein Atlas with these methods to provide an antibody validation resource for providers and users.
Keywords	Science ; Q
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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