ILC1 drive intestinal epithelial and matrix remodelling

GM Jowett and MDA Norman and TTL Yu and PR Arevalo and D Hoogland and ST Lust and E Read and E Hamrud and NJ Walters and U Niazi and MWH Chung and D Marciano and OS Omer and T Zabinski and D Danovi and GM Lord and J Hilborn and ND Evans and CA Dreiss and L Bozec and OP Oommen and CD Lorenz and RMP da Silva and JF Neves and E Gentleman, NATURE MATERIALS, 20, 250-+ (2021).

DOI: 10.1038/s41563-020-0783-8

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 beta 1, 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. Type-1 innate lymphoid cells have been shown to drive intestinal epithelial proliferation and extracellular matrix remodelling through TGF-beta 1 secretion, which could exacerbate inflammatory bowel disease comorbidities such as cancer and fibrosis.

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