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A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

R. Hugh F. Bender, Benjamen T. O’Donnell, Bhupinder Shergill, Brittany Q. Pham, Damie J. Juat, Michaela S. Hatch, Venktesh S. Shirure, Matthew Wortham, Kim-Vy Nguyen-Ngoc, Yesl Jun, Roberto Gaetani, Karen L. Christman, Luc Teyton, Steven C. George, Maike Sander, Christopher C.W. Hughes
doi: https://doi.org/10.1101/2021.12.21.473744
R. Hugh F. Bender
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
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Benjamen T. O’Donnell
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
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Bhupinder Shergill
2Dept. of Biomedical Engineering, University of California, Davis
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Brittany Q. Pham
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
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Damie J. Juat
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
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Michaela S. Hatch
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
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Venktesh S. Shirure
2Dept. of Biomedical Engineering, University of California, Davis
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Matthew Wortham
3Pediatric Diabetes Research Center, Dept. of Pediatrics, University of California, San Diego
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Kim-Vy Nguyen-Ngoc
3Pediatric Diabetes Research Center, Dept. of Pediatrics, University of California, San Diego
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Yesl Jun
3Pediatric Diabetes Research Center, Dept. of Pediatrics, University of California, San Diego
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Roberto Gaetani
5Dept. of Bioengineering, University of California, San Diego
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Karen L. Christman
5Dept. of Bioengineering, University of California, San Diego
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Luc Teyton
6Dept. of Immunology & Microbiology, The Scripps Research Institute
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Steven C. George
2Dept. of Biomedical Engineering, University of California, Davis
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Maike Sander
3Pediatric Diabetes Research Center, Dept. of Pediatrics, University of California, San Diego
4Dept. of Cellular & Molecular Medicine, University of California, San Diego
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Christopher C.W. Hughes
1Dept. of Molecular Biology & Biochemistry, University of California, Irvine
7Dept. of Biomedical Engineering, University of California, Irvine
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  • For correspondence: cchughes@uci.edu
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ABSTRACT

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively by β cells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of islet β cells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlying β cell damage in diabetes rely on in vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing — key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel, ex vivo platform for studying human islet biology in both health and disease.

Competing Interest Statement

C.C.W.H. and S.C.G. are co-founders and shareholders of Aracari Biosciences Inc., a biotechnology start-up company focused on commercializing the core VMO technology described here. R.H.F.B is a part-time employee of Aracari Biosciences Inc. and receives stock and financial compensation. The terms of these arrangements have been reviewed and approved by the University of California, Irvine in accordance with its conflict-of-interest policies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 23, 2021.
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A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction
R. Hugh F. Bender, Benjamen T. O’Donnell, Bhupinder Shergill, Brittany Q. Pham, Damie J. Juat, Michaela S. Hatch, Venktesh S. Shirure, Matthew Wortham, Kim-Vy Nguyen-Ngoc, Yesl Jun, Roberto Gaetani, Karen L. Christman, Luc Teyton, Steven C. George, Maike Sander, Christopher C.W. Hughes
bioRxiv 2021.12.21.473744; doi: https://doi.org/10.1101/2021.12.21.473744
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A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction
R. Hugh F. Bender, Benjamen T. O’Donnell, Bhupinder Shergill, Brittany Q. Pham, Damie J. Juat, Michaela S. Hatch, Venktesh S. Shirure, Matthew Wortham, Kim-Vy Nguyen-Ngoc, Yesl Jun, Roberto Gaetani, Karen L. Christman, Luc Teyton, Steven C. George, Maike Sander, Christopher C.W. Hughes
bioRxiv 2021.12.21.473744; doi: https://doi.org/10.1101/2021.12.21.473744

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