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ILC1 drive intestinal epithelial and matrix remodelling

Nature Materials volume 20, pages 250–259 (2021)Cite this article

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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 develop gut organoid cocultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate that murine and human ILC1 secrete transforming growth factor β1, 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.

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Fig. 1: ILC1 impact intestinal organoid gene expression.
Fig. 2: ILC1 impact epithelial crypt gene expression through TGF-β1 secretion.
Fig. 3: Human ILC1 drive CD44v6 expression in HIO.
Fig. 4: Modular PEG-based hydrogels form at low polymer concentrations and support HIO viability and phenotype.
Fig. 5: aILC1 drive HIO matrix remodelling in synthetic hydrogels.
Fig. 6: Overview of proposed impact of ILC1 on gut organoids.

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Data availability

The differentially expressed genes identified in the RNA-seq dataset are available in Supplementary Dataset 1. The data have also been deposited with GEO at https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA641809 and at https://github.com/uhkniazi/BRC_Organoids_Geraldine. All other data supporting the findings of this study are available within the article and its supplementary information files or from the corresponding authors upon reasonable request.

Code availability

All codes used to analyse the molecular dynamics simulations were tools that were built in house. All codes with accompanying documentation on how to use them are freely accessible at https://github.com/Lorenz-Lab-KCL and https://nms.kcl.ac.uk/lorenz.lab/wp/. R code for determining α from mean squared displacement data for microrheology is available in Supplementary Dataset 2 and is freely accessible at https://github.com/eileengentleman/Microrheology-code.

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Acknowledgements

G.M.J. acknowledges a PhD fellowship from the Wellcome Trust (203757/Z/16/A) and a BRC Bright Sparks Precision Medicine Early Career Research Award. E.G. acknowledges a Philip Leverhulme Prize from the Leverhulme Trust. J.F.N. acknowledges a Marie Skłodowska-Curie Fellowship, a King’s Prize fellowship, an RCUK/UKRI Rutherford Fund fellowship (MR/R024812/1) and a Seed Award in Science from the Wellcome Trust (204394/Z/16/Z). J.F.N. and E.G. are grateful to the Gut Human Organoid Platform (Gut-HOP) at King’s College London, which is supported financially by a King’s Together Strategic Award. M.D.A.N. is supported by a PhD studentship funded by the BBSRC London Interdisciplinary Doctoral Programme. E.R. acknowledges a PhD fellowship from the Wellcome Trust (215027/Z/18/Z). S.T.L. gratefully acknowledges the UK Medical Research Council (MR/N013700/1) for funding through the MRC Doctoral Training Partnership in Biomedical Sciences at King’s College London. G.M.L. is supported by grants awarded by the Wellcome Trust (091009) and the Medical Research Council (MR/M003493/1 and MR/K002996/1). N.J.W. acknowledges a Jane and Aatos Erkko Foundation Personal Scholarship. R.M.P.d.S. acknowledges a King’s Prize fellowship supported by the Wellcome Trust (Institutional Strategic Support Fund), King’s College London and the London Law Trust. Via C.D.L.’s membership in the UK’s HEC Materials Chemistry Consortium, which is funded by EPSRC (EP/L000202, EP/R029431), this work used the ARCHER UK National Supercomputing Service (http://www.archer.ac.uk) and the UK Materials and Molecular Modelling Hub (MMM Hub) for computational resources, which is partially funded by EPSRC (EP/P020194/1), to carry out the molecular dynamics simulations. We also thank the BRC flow cytometry core team, and acknowledge financial support from the Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We thank C. Dondi, D. Foyt and O. Birch for technical assistance. We are grateful to J. Spencer and K. Schultz for helpful conversations about CD44 and microrheology, R. Beavil and A. Beavil for technical support with size exclusion chromatography–high-performance liquid chromatography, H. Sinclair from the Microscopy Innovation Centre for assistance acquiring microrheology data, R. Thorogate and the London Centre for Nanotechnology for assistance with AFM, R. A. Atkinson and the NMR Facility of the Centre for Biomolecular Spectroscopy at King’s College London, which was established with awards from the Wellcome Trust, British Heart Foundation and King’s College London, for assistance with NMR, and S. Engledow at the Oxford Wellcome Genomics Centre for processing the RNA-seq samples. Finally, we thank L. Roberts, E. Slatery and R. Sancho for critically reading this manuscript and providing helpful feedback.

Author information

Author notes

  1. These authors contributed equally: Michael D. A. Norman, Tracy T. L. Yu, Joana F. Neves, Eileen Gentleman.

Authors and Affiliations

  1. Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK

    Geraldine M. Jowett, Michael D. A. Norman, Tracy T. L. Yu, Suzette T. Lust, Eva Hamrud, Daniele Marciano, Ricardo M. P. da Silva & Eileen Gentleman

  2. Centre for Host Microbiome Interactions, King’s College London, London, UK

    Geraldine M. Jowett, Patricia Rosell Arévalo, Emily Read, Matthew Wai Heng Chung, Tomasz Zabinski & Joana F. Neves

  3. Wellcome Trust Cell Therapies and Regenerative Medicine PhD Programme, London, UK

    Geraldine M. Jowett, Emily Read, Eva Hamrud & Matthew Wai Heng Chung

  4. Centre for Stem Cells & Regenerative Medicine, King’s College London, London, UK

    Geraldine M. Jowett, Eva Hamrud, Matthew Wai Heng Chung & Davide Danovi

  5. Department of Chemistry, King’s College London, London, UK

    Dominique Hoogland

  6. BioMediTech, Tampere University Tampere Finland, Helsinki, Finland

    Nick J. Walters

  7. Natural Resources Institute Finland, Helsinki, Finland

    Nick J. Walters

  8. Guy’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

    Umar Niazi

  9. School of Immunology and Microbial Sciences, King’s College London, London, UK

    Omer S. Omer

  10. Department of Gastroenterology, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK

    Omer S. Omer

  11. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Graham M. Lord

  12. Department of Chemistry, Ångström Laboratory, Uppsala University, Uppsala, Sweden

    Jöns Hilborn

  13. Bone 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

    Nicholas D. Evans

  14. Institute of Pharmaceutical Science, King’s College London, London, UK

    Cécile A. Dreiss

  15. Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

    Laurent Bozec

  16. Bioengineering and Nanomedicine Lab, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Oommen P. Oommen

  17. Department of Physics, King’s College London, London, UK

    Christian D. Lorenz

  18. i3S—Instituto de Investigação e Inovação em Saúde—and INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

    Ricardo M. P. da Silva

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  1. Geraldine M. Jowett
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Contributions

G.M.J., M.D.A.N., T.T.L.Y., L.B., J.F.N. and E.G. developed experimental protocols, conducted experiments and analysed data. G.M.J. designed, conducted and analysed all murine and human experiments. T.T.L.Y., J.H., O.P.O., N.J.W., N.D.E., E.G. and R.M.P.d.S. designed and optimized the hydrogel synthesis. R.M.P.d.S. designed peptide sequences. M.D.A.N., D.H., S.T.L., T.T.L.Y., G.M.J., C.A.D. and D.M. characterized the hydrogel. S.T.L. and C.D.L. performed the molecular dynamics simulations. G.M.J. and J.F.N. designed the RNA-seq experiment, and U.N. and M.W.H.C. provided bioinformatic analysis. G.M.J., P.R.A., E.R. and T.Z. performed tissue isolations. G.M.J., E.G., M.D.A.N. and E.H. designed and conducted microrheology and AFM experiments. G.M.L., O.S.O. and D.D. contributed reagents, biopsies and hiPSC lines. G.M.J., E.G. and J.F.N. conceived the ideas, initiated the project, interpreted the data and prepared the manuscript. E.G. and J.F.N. supervised the project. All authors revised the manuscript.

Corresponding authors

Correspondence to Joana F. Neves or Eileen Gentleman.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–28 and Tables 1 and 2.

Reporting Summary

Supplementary Data 1

RNA-sequencing dataset.

Supplementary Data 2

R code for microrheology.

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Jowett, G.M., Norman, M.D.A., Yu, T.T.L. et al. ILC1 drive intestinal epithelial and matrix remodelling. Nat. Mater. 20, 250–259 (2021). https://doi.org/10.1038/s41563-020-0783-8

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