Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation
- City of Hope, United States
- California State University, Long Beach, United States
- University of California, Davis, United States
- University of British Columbia, Canada
Abstract
Pancreatic islets are 3-dimensional cell aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Cell aggregation is essential for islet endocrine function; however, it remains unclear how developing islets establish aggregation. By combining genetic animal models, imaging tools, and gene expression profiling, we demonstrate that islet aggregation is regulated by extracellular matrix signaling and cell-cell adhesion. Islet endocrine cell-specific inactivation of extracellular matrix receptor Integrin β1 disrupted blood vessel interactions but promoted cell-cell adhesion and the formation of larger islets. In contrast, ablation of cell-cell adhesion molecule α-Catenin promoted blood vessel interactions yet compromised islet clustering. Simultaneous removal of Integrin β1 and α-Catenin disrupts islet aggregation and the endocrine cell maturation process, demonstrating that establishment of islet aggregates is essential for functional maturation. Our study provides new insights into understanding the fundamental self-organizing mechanism for islet aggregation, architecture, and functional maturation.
Data availability
1) Sequencing data have been deposited in GEO under accession numbers#(GSE153187, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153187). access token: epslqeyqfhmbzsr(GSE190788, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE190788). access token:clcvcqmottkvvsrTokens for reviewers are provided.We have not made these data publicly available yet. Once the manuscript is accepted for publication, we will release the data to public. As well, two spreed sheets of the RNA-seq data are provided as Supplementary Tables S1 and S2.2) All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures3) Each experiment were replicated in laboratory at least three times.Samples were allocated into experimental groups either pairwise (for WT cells with or without treatment) or based on the genotypes (WT vs KO).All the replicate information and the number of replicates and sample sizes can be found in figure legends is described in "List of n and Statistical V2 " in the Supplementary file.4) Key Resource table is provided in the Supplementary file
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The role of Itgb1 in islet developmentNCBI Gene Expression Omnibus, GSE153187.
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Investigating the role of cell adhesion molecule alpha-catenin during islet developmentNCBI Gene Expression Omnibus, GSE190788.
Article and author information
Author details
Maricela Maldonado
Funding
The California Institute for Regernerative Medicine (Training Grant EDUC4-12772)
- Wilma Tixi
NIH/NIDDK (1R01DK119590)
- Hung Ping Shih
JDRF postdoctoral fellowship (-PDF-2019-742-A-N)
- Maricela Maldonado
NSERC Discovery Grant (RGPIN-2016-04276)
- Janel L Kopp
CIHR New Investigator Award (Msh-147794)
- Janel L Kopp
MSFHR Scholar Award (18309)
- Janel L Kopp
NIH/NIDDK (1R01DK110276)
- Mark O Huising
NIH/NIDDK (1R01DK120523)
- Sangeeta Dhawan
Human Islet 883 Research Network New investigator Award (UC4DK104162))
- Sangeeta Dhawan
Wanek Family Foundation to Cure Type 1 Diabetes
- Sangeeta Dhawan
- Hung Ping Shih
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments described herein were approved by the City of Hope Institutional Animal Care and Use Committee (Protocol 15041) and Institutional Biosafety Committee (Protocol 16002).
Reviewing Editor
- Lori Sussel, University of Colorado Anschutz Medical Campus, United States
Version history
- Preprint posted: April 28, 2022 (view preprint)
- Received: June 7, 2023
- Accepted: July 12, 2023
- Accepted Manuscript published: August 23, 2023 (version 1)
- Version of Record published: September 6, 2023 (version 2)
Copyright
© 2023, Tixi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation
eLife 12:e90006.
https://doi.org/10.7554/eLife.90006
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