The SARS-CoV-2 Receptor ACE2 is Expressed in Mouse Pericytes but Not Endothelial Cells: Implications for COVID-19 Vascular Research

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2022 Apr 22

PMID 35452595

Authors

Lars Muhl

Liqun He

Ying Sun

Maarja Andaloussi Mae

Riikka Pietila

Jianping Liu

Guillem Genove

Lei Zhang

Yuan Xie

Stefanos Leptidis

Giuseppe Mocci

Simon Stritt

Ahmed Osman

Andrey Anisimov

Karthik Amudhala Hemanthakumar

Markus Rasanen

Emil M Hansson

Johan Bjorkegren

Michael Vanlandewijck

Klas Blomgren

Taija Makinen

Xiao-Rong Peng

Yizhou Hu

Patrik Ernfors

Thomas D Arnold

Kari Alitalo

Urban Lendahl

Christer Betsholtz

Affiliations

Soon will be listed here.

Abstract

Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is important to learn where the SARS-CoV-2 receptor ACE2 is expressed. Here we mapped ACE2 expression during mouse postnatal development and in adulthood. Pericytes in the CNS, heart, and pancreas express ACE2 strongly, as do perineurial and adrenal fibroblasts, whereas endothelial cells do not at any location analyzed. In a number of other organs, pericytes do not express ACE2, including in the lung where ACE2 instead is expressed in bronchial epithelium and alveolar type II cells. The onset of ACE2 expression is organ specific: in bronchial epithelium already at birth, in brain pericytes before, and in heart pericytes after postnatal day 10.5. Establishing the vascular localization of ACE2 expression is central to correctly interpret data from modeling COVID-19 in the mouse and may shed light on the cause of vascular COVID-19 complications.

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References

Gerber D, Pereira J, Gerber J, Tan G, Dimitrieva S, Yanguez E . Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT). Elife. 2021; 10. PMC: 8064760. DOI: 10.7554/eLife.58591. View

Burkert F, Lanser L, Bellmann-Weiler R, Weiss G . Coronavirus Disease 2019: Clinics, Treatment, and Prevention. Front Microbiol. 2021; 12:761887. PMC: 8631905. DOI: 10.3389/fmicb.2021.761887. View

Ackermann M, Verleden S, Kuehnel M, Haverich A, Welte T, Laenger F . Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020; 383(2):120-128. PMC: 7412750. DOI: 10.1056/NEJMoa2015432. View

Rauch A, Dupont A, Goutay J, Caplan M, Staessens S, Moussa M . Endotheliopathy Is Induced by Plasma From Critically Ill Patients and Associated With Organ Failure in Severe COVID-19. Circulation. 2020; 142(19):1881-1884. PMC: 7643783. DOI: 10.1161/CIRCULATIONAHA.120.050907. View

He L, Vanlandewijck M, Raschperger E, Mae M, Jung B, Lebouvier T . Analysis of the brain mural cell transcriptome. Sci Rep. 2016; 6:35108. PMC: 5057134. DOI: 10.1038/srep35108. View

Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H . Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2):631-7. PMC: 7167720. DOI: 10.1002/path.1570. View

Geurts M, van der Vaart J, Beumer J, Clevers H . The Organoid Platform: Promises and Challenges as Tools in the Fight against COVID-19. Stem Cell Reports. 2021; 16(3):412-418. PMC: 7940129. DOI: 10.1016/j.stemcr.2020.11.009. View

Deinhardt-Emmer S, Bottcher S, Haring C, Giebeler L, Henke A, Zell R . SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction. J Virol. 2021; 95(10). PMC: 8139673. DOI: 10.1128/JVI.00110-21. View

. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018; 562(7727):367-372. PMC: 6642641. DOI: 10.1038/s41586-018-0590-4. View

10.

Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer R, Stahl M . Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell. 2020; 181(4):905-913.e7. PMC: 7181998. DOI: 10.1016/j.cell.2020.04.004. View

11.

Sungnak W, Huang N, Becavin C, Berg M, Queen R, Litvinukova M . SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020; 26(5):681-687. PMC: 8637938. DOI: 10.1038/s41591-020-0868-6. View

12.

Muus C, Luecken M, Eraslan G, Sikkema L, Waghray A, Heimberg G . Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med. 2021; 27(3):546-559. PMC: 9469728. DOI: 10.1038/s41591-020-01227-z. View

13.

Vanlandewijck M, He L, Mae M, Andrae J, Ando K, Del Gaudio F . A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018; 554(7693):475-480. DOI: 10.1038/nature25739. View

14.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

15.

Singh D, Winocour P, Farrington K . Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol. 2008; 4(4):216-26. DOI: 10.1038/ncpneph0757. View

16.

Chen L, Li X, Chen M, Feng Y, Xiong C . The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 2020; 116(6):1097-1100. PMC: 7184507. DOI: 10.1093/cvr/cvaa078. View

17.

Cantuti-Castelvetri L, Ojha R, Pedro L, Djannatian M, Franz J, Kuivanen S . Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020; 370(6518):856-860. PMC: 7857391. DOI: 10.1126/science.abd2985. View

18.

Guo M, Tao W, Flavell R, Zhu S . Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat Rev Gastroenterol Hepatol. 2021; 18(4):269-283. PMC: 7883337. DOI: 10.1038/s41575-021-00416-6. View

19.

Fignani D, Licata G, Brusco N, Nigi L, Grieco G, Marselli L . SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic -Cells and in the Human Pancreas Microvasculature. Front Endocrinol (Lausanne). 2020; 11:596898. PMC: 7691425. DOI: 10.3389/fendo.2020.596898. View

20.

Nicin L, Abplanalp W, Mellentin H, Kattih B, Tombor L, John D . Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J. 2020; 41(19):1804-1806. PMC: 7184464. DOI: 10.1093/eurheartj/ehaa311. View