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SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature

Daniela Fignani, Giada Licata, Noemi Brusco, Laura Nigi, Giuseppina E. Grieco, Lorella Marselli, Lut Overbergh, Conny Gysemans, Maikel L. Colli, Piero Marchetti, Chantal Mathieu, Decio L. Eizirik, Guido Sebastiani, Francesco Dotta
doi: https://doi.org/10.1101/2020.07.23.208041
Daniela Fignani
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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Giada Licata
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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Noemi Brusco
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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Laura Nigi
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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Giuseppina E. Grieco
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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Lorella Marselli
4Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Lut Overbergh
5Clinical and Experimental Endocrinology (CEE), Katholieke Universiteit Leuven (KULEUVEN), Leuven, Belgium
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Conny Gysemans
5Clinical and Experimental Endocrinology (CEE), Katholieke Universiteit Leuven (KULEUVEN), Leuven, Belgium
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Maikel L. Colli
6ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
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Piero Marchetti
4Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Chantal Mathieu
5Clinical and Experimental Endocrinology (CEE), Katholieke Universiteit Leuven (KULEUVEN), Leuven, Belgium
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Decio L. Eizirik
6ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
7Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
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Guido Sebastiani
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
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  • For correspondence: sebastianiguido@gmail.com
Francesco Dotta
1Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
2Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
3Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
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Abstract

Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2), is a necessary step for SARS-CoV-2 infection permissiveness. In the light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyse ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies.

Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing β-cells. ACE2 is also is highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human β-cells.

Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increases ACE2 expression in the β-cell line EndoC-βH1 and in primary human pancreatic islets.

Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct β-cell virus tropism.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Joint first co-authorship

  • ↵# Share last co-authorship

  • In the present manuscript, following the increasing evidence of: a) an association between COVID-19 infection and diabetes mellitus, both in terms of acute hyperglycaemia observed at admission in a substantial percentage of SARS-CoV-2 infected subjects, regardless of the past medical history of diabetes, and of the association between impaired glycaemic control and increased risk of severe COVID-19 clinical manifestations; b) the demonstration that expression of Angiotensin I-Converting Enzyme type 2 (ACE2) on target cells is a necessary step for SARS-CoV-2 infection permissiveness; we aimed at analyzing ACE2 expression in human pancreas with a particular focus on the islet endocrine cell subsets. To this end, we took advantage of the access to precious pancreatic tissue samples from multiorgan donors obtained through the EU-funded INNODIA network EUnPOD biobank to thoroughly analyze ACE2, both at mRNA and protein level. An additional set of experiments was performed on the human β-cell line EndoC-βH1, in order to gain insight into the potential mechanisms involved in the regulation of ACE2 expression. Specifically, we demonstrated that: - Human pancreatic islets express SARS-CoV-2 receptor ACE2. - In human pancreatic islets, ACE2 is preferentially expressed by insulin secreting β-cells. - In human β-cells, ACE2 expression is increased upon cytokine-induced inflammatory stress, thus putatively suggesting an enhancement of β-cell sensitivity to SARS-CoV-2 in the presence of proinflammatory conditions. Taken together, our data uncover a link between SARS-CoV-2 infection, inflammation and diabetes mellitus, through direct β-cell virus tropism via ACE2.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature
Daniela Fignani, Giada Licata, Noemi Brusco, Laura Nigi, Giuseppina E. Grieco, Lorella Marselli, Lut Overbergh, Conny Gysemans, Maikel L. Colli, Piero Marchetti, Chantal Mathieu, Decio L. Eizirik, Guido Sebastiani, Francesco Dotta
bioRxiv 2020.07.23.208041; doi: https://doi.org/10.1101/2020.07.23.208041
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SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature
Daniela Fignani, Giada Licata, Noemi Brusco, Laura Nigi, Giuseppina E. Grieco, Lorella Marselli, Lut Overbergh, Conny Gysemans, Maikel L. Colli, Piero Marchetti, Chantal Mathieu, Decio L. Eizirik, Guido Sebastiani, Francesco Dotta
bioRxiv 2020.07.23.208041; doi: https://doi.org/10.1101/2020.07.23.208041

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