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ILC1 drive intestinal epithelial and matrix remodelling

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)250-259
Number of pages10
JournalNATURE MATERIALS
Volume20
Issue number2
Early online date7 Sep 2020
DOIs
Accepted/In press23 Jul 2020
E-pub ahead of print7 Sep 2020
Published28 Feb 2021

Bibliographical note

Funding Information: hMSC attachment on 2D hydrogel surfaces. Human bone-marrow-derived stromal cells (hMSC) were obtained from the Imperial College Healthcare Tissue Bank (ICHTB, Human Tissue Authority licence 12275). ICHTB is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. ICHTB is approved by the UK National Research Ethics Service to release human material for research (12/WA/0196) as previously described51. The samples for this project were issued from subcollection R16052. Fifty-microlitre 5% hydrogels formed with 5-K PEG-4VS were formed in six-well plates and 24-mm Sigmacote-treated coverslips placed on top. After hydrogel formation, 5,000hMSCcm−2were seeded and allowed to adhere for 2h prior to the addition of basal culture medium. After 24h, hMSC were fixed in 4% paraformaldehyde, permeabilized in 0.2% (v/v) Triton X-100 and stained with phalloidin–tetramethylrhodamine isothiocyanate (Sigma) and DAPI. Cells were imaged on an Olympus inverted fluorescent microscope equipped with a Jenoptik camera. Funding Information: 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. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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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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