Controlled aggregation of primary human pancreatic islet cells leads to glucose‐responsive pseudoislets comparable to native islets
Open accessAbstract
Clinical islet transplantation is a promising treatment for patients with type 1 diabetes. However, pancreatic islets vary in size and shape affecting their survival and function after transplantation because of mass transport limitations. To reduce diffusion restrictions and improve islet cell survival, the generation of islets with optimal dimensions by dispersion followed by reassembly of islet cells, can help limit the length of diffusion pathways. This study describes a microwell platform that supports the controlled and reproducible production of three‐dimensional pancreatic cell clusters of human donor islets. We observed that primary human islet cell aggregates with a diameter of 100–150 μm consisting of about 1000 cells best resembled intact pancreatic islets as they showed low apoptotic cell death (<2%), comparable glucose‐responsiveness and increasing PDX 1, MAFA and INSULIN gene expression with increasing aggregate size. The re‐associated human islet cells showed an a‐typical core shell configuration with beta cells predominantly on the outside unlike human islets, which became more randomized after implantation similar to native human islets. After transplantation of these islet cell aggregates under the kidney capsule of immunodeficient mice, human C‐peptide was detected in the serum indicating that beta cells retained their endocrine function similar to human islets. The agarose microwell platform was shown to be an easy and very reproducible method to aggregate pancreatic islet cells with high accuracy providing a reliable tool to study cell–cell interactions between insuloma and/or primary islet cells.
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Larger islets have been known to form necrotic centers because of a lack of oxygen and nutrient diffusion; other studies have found that islets best maintain cellular identity and function when they have a size of ca. 100-150 microns.
“Larger islets have been known to form necrotic centers because of a lack of oxygen and nutrient diffusion; other studies have found that islets best maintain cellular identity and function when they have a size of ca. 100–150 microns177.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [177]
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Towards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409 · see citing works
- Authors
- Hilderink, J., Spijker, S., Carlotti, F., Lange, L., Engelse, M., van Blitterswijk, C., de Koning, E., Karperien, M., & van Apeldoorn, A.
- Affiliations
- University of Twente (NL)
- Department of Nephrology Leiden University Medical Center Leiden The Netherlands
- Leiden University Medical Center (NL)
- Department of Tissue Regeneration University of Twente Enschede The Netherlands
- Department of Developmental Bioengineering University of Twente Enschede The Netherlands
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2015-03-17
- Volume
- 19
- Issue
- 8
- Pages
- 1836-1846
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC4549034
- OpenAlex
- W2160639244
- Cited by
- 83
- References
- 40
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 4 · 2022: 13 · 2021: 11 · 2020: 5 · 2019: 12 · 2018: 6 · 2017: 9 · 2016: 6
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- University of Twente Research Information (publishedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- University of Twente Research Information (submittedVersion)
- Funders
- Dutch Diabetes Research Initiative
- Dutch Diabetes Research Foundation
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- pseudoislets, islet transplantation, type 1 diabetes, beta-cell function, glucose responsiveness, C-peptide, islet cell survival, diffusion limitation, PDX1, MafA, insulin gene expression
- MeSH terms
- Animals, Cell Aggregation, Cell Survival, Cells, Cultured, Female, Glucose, Humans, Insulinoma, Islets of Langerhans, Male, Middle Aged, Reproducibility of Results, Mice, SCID, Cell Line, Tumor, Cell Size
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