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ILC1-derived TGFβ1 drives intestinal remodelling

View ORCID ProfileGeraldine M. Jowett, Michael D. A. Norman, Tracy T. L. Yu, Patricia Rosell Arévalo, View ORCID ProfileDominique Hoogland, Suzette Lust, View ORCID ProfileEmily Read, View ORCID ProfileEva Hamrud, View ORCID ProfileNick J. Walters, Umar Niazi, View ORCID ProfileMatthew Wai Heng Chung, Daniele Marciano, View ORCID ProfileOmer Serhan Omer, Tomasz Zabinski, View ORCID ProfileDavide Danovi, View ORCID ProfileGraham M. Lord, Jöns Hilborn, View ORCID ProfileNicholas D. Evans, View ORCID ProfileCécile A. Dreiss, View ORCID ProfileLaurent Bozec, Oommen P. Oommen, View ORCID ProfileChristian D. Lorenz, Ricardo M.P. da Silva, View ORCID ProfileJoana F. Neves, View ORCID ProfileEileen Gentleman
doi: https://doi.org/10.1101/2020.04.20.051805
Geraldine M. Jowett
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
3Wellcome Trust Cell Therapies and Regenerative Medicine PhD programme
4Centre for Stem Cells & Regenerative Medicine, King’s College London, London, SE1 9RT, UK
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Michael D. A. Norman
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
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Tracy T. L. Yu
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
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Patricia Rosell Arévalo
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
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Dominique Hoogland
5Department of Chemistry, King’s College London, London SE1 1DB, UK
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Suzette Lust
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
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Emily Read
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
3Wellcome Trust Cell Therapies and Regenerative Medicine PhD programme
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Eva Hamrud
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
3Wellcome Trust Cell Therapies and Regenerative Medicine PhD programme
4Centre for Stem Cells & Regenerative Medicine, King’s College London, London, SE1 9RT, UK
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Nick J. Walters
6BioMediTech, Tampere University, 33014 Tampereen yliopisto, Finland, and Natural Resources Institute Finland, 00790 Helsinki, Finland
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Umar Niazi
7Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London National Institute for Health Research Biomedical Research Centre Translational Bioinformatics Platform, Guy’s Hospital, London, UK
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Matthew Wai Heng Chung
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
3Wellcome Trust Cell Therapies and Regenerative Medicine PhD programme
4Centre for Stem Cells & Regenerative Medicine, King’s College London, London, SE1 9RT, UK
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Daniele Marciano
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
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Omer Serhan Omer
8School of Immunology and Microbial Sciences, King’s College London, London, UK
9Department of Gastroenterology, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK
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Tomasz Zabinski
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
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Davide Danovi
4Centre for Stem Cells & Regenerative Medicine, King’s College London, London, SE1 9RT, UK
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Graham M. Lord
10Faculty of Biology, Medicine and Health, University of Manchester, M13 9NT, UK
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Jöns Hilborn
11Department of Chemistry, Ångström Laboratory, Uppsala University, Uppsala 75121, Sweden
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Nicholas D. Evans
12Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, Institute of Developmental Sciences, University of Southampton, Southampton, UK
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Cécile A. Dreiss
13Institute of Pharmaceutical Science, Franklin-Wilkins Building, King’s College London, London SE1 9NH, UK
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Laurent Bozec
14Faculty of Dentistry, University of Toronto, Toronto, Canada
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Oommen P. Oommen
15Bioengineering and Nanomedicine Lab, Faculty of Medicine and Health Technology, Tampere University, 33720 Tampere, Finland
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Christian D. Lorenz
16Department of Physics, King’s College London, London WC2R 2LS, UK
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Ricardo M.P. da Silva
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
17i3S - Instituto de Investigação e Inovação em Saúde and INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal
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Joana F. Neves
2Centre for Host Microbiome Interactions, King’s College London, London, SE1 9RT, UK
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  • For correspondence: eileen.gentleman@kcl.ac.uk joana.pereira_das_neves@kcl.ac.uk
Eileen Gentleman
1Centre for Craniofacial and Regenerative Biology, King’s College London, London SE1 9RT, UK
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  • ORCID record for Eileen Gentleman
  • For correspondence: eileen.gentleman@kcl.ac.uk joana.pereira_das_neves@kcl.ac.uk
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Abstract

Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we developed gut organoid co-cultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate for the first time that murine and human ILC1 secrete TGFβ1, driving expansion of CD44v6+ epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial-mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues.

Competing Interest Statement

The authors have declared no competing interest.

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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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 22, 2020.
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ILC1-derived TGFβ1 drives intestinal remodelling
Geraldine M. Jowett, Michael D. A. Norman, Tracy T. L. Yu, Patricia Rosell Arévalo, Dominique Hoogland, Suzette Lust, Emily Read, Eva Hamrud, Nick J. Walters, Umar Niazi, Matthew Wai Heng Chung, Daniele Marciano, Omer Serhan Omer, Tomasz Zabinski, Davide Danovi, Graham M. Lord, Jöns Hilborn, Nicholas D. Evans, Cécile A. Dreiss, Laurent Bozec, Oommen P. Oommen, Christian D. Lorenz, Ricardo M.P. da Silva, Joana F. Neves, Eileen Gentleman
bioRxiv 2020.04.20.051805; doi: https://doi.org/10.1101/2020.04.20.051805
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ILC1-derived TGFβ1 drives intestinal remodelling
Geraldine M. Jowett, Michael D. A. Norman, Tracy T. L. Yu, Patricia Rosell Arévalo, Dominique Hoogland, Suzette Lust, Emily Read, Eva Hamrud, Nick J. Walters, Umar Niazi, Matthew Wai Heng Chung, Daniele Marciano, Omer Serhan Omer, Tomasz Zabinski, Davide Danovi, Graham M. Lord, Jöns Hilborn, Nicholas D. Evans, Cécile A. Dreiss, Laurent Bozec, Oommen P. Oommen, Christian D. Lorenz, Ricardo M.P. da Silva, Joana F. Neves, Eileen Gentleman
bioRxiv 2020.04.20.051805; doi: https://doi.org/10.1101/2020.04.20.051805

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