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.

类器官可以揭示受控微环境中复杂组织和稀有细胞类型之间的动态相互作用。在这里，我们开发了具有 1 型先天性淋巴细胞 (ILC1) 的肠道类器官共培养物，以剖析它们在发炎肠道中积累的影响。我们证明小鼠和人类 ILC1 分泌转化生长因子 β1，驱动 CD44v6 ^+的扩增上皮隐窝。ILC1 还表达 MMP9 并驱动指示细胞外基质重塑的基因特征。因此，我们将人类上皮-间充质肠道类器官封装在 MMP 敏感的合成水凝胶中，该水凝胶旨在在低聚合物浓度下形成高效网络。利用这个定义的系统，我们证明了 ILC1 驱动基质软化和硬化，我们建议这是通过平衡的基质降解和沉积发生的。我们的平台使我们能够阐明以前未描述的 ILC1 与其微环境之间的相互作用，这表明它们在发炎的患者组织中富集时可能会加剧纤维化和肿瘤生长。