Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

  1. Wilma Tixi
  2. Maricela Maldonado
  3. Ya-Ting Chang
  4. Amy Chiu
  5. Wilson Yeung
  6. Nazia Parveen
  7. Michael S Nelson
  8. Ryan Hart
  9. Shihao Wang
  10. Wu Jih Hsu
  11. Patrick Fueger
  12. Janel L Kopp
  13. Mark O Huising
  14. Sangeeta Dhawan
  15. Hung Ping Shih  Is a corresponding author
  1. City of Hope, United States
  2. California State University, Long Beach, United States
  3. University of California, Davis, United States
  4. 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

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Wilma Tixi

    Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Maricela Maldonado

    Department of Biomedical Engineering, California State University, Long Beach, Long Beach, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4682-6900
  3. Ya-Ting Chang

    Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amy Chiu

    Department of Translational Research and Cellular Therapeutic, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Wilson Yeung

    Department of Translational Research and Cellular Therapeutic, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nazia Parveen

    Department of Translational Research and Cellular Therapeutic, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Michael S Nelson

    Light Microscopy Core, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0480-5597
  8. Ryan Hart

    Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shihao Wang

    Department of Cellular and Physiological Sciences, University of British Columbia, British Columbia, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Wu Jih Hsu

    Department of Cellular and Physiological Sciences, University of British Columbia, British Columbia, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5385-9079
  11. Patrick Fueger

    Department of Molecular and Cellular Endocrinology, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Janel L Kopp

    Department of Cellular and Physiological Sciences, University of British Columbia, British Columbia, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1875-3401
  13. Mark O Huising

    Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Sangeeta Dhawan

    Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Hung Ping Shih

    Department of Translational Research and Cellular Therapeutics, City of Hope, Duarte, United States
    For correspondence
    hshih@coh.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3035-5841

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).

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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  1. Wilma Tixi
  2. Maricela Maldonado
  3. Ya-Ting Chang
  4. Amy Chiu
  5. Wilson Yeung
  6. Nazia Parveen
  7. Michael S Nelson
  8. Ryan Hart
  9. Shihao Wang
  10. Wu Jih Hsu
  11. Patrick Fueger
  12. Janel L Kopp
  13. Mark O Huising
  14. Sangeeta Dhawan
  15. Hung Ping Shih
(2023)
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

Share this article

https://doi.org/10.7554/eLife.90006

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