The intestinal barrier is a complex structure that allows the absorption of nutrients while ensuring protection against intestinal pathogens and balanced immunity. The development and maintenance of a functional intestinal barrier is a multifactorial process that is only partially understood. Here we review novel findings on the emerging role of mesenchymal cells in this process using insights gained from lineage tracing approaches, Cre-based gene deletion, and single-cell transcriptomics. The current evidence points toward a key organizer role for distinct mesenchymal lineages in intestinal development and homeostasis, regulating both epithelial and immune components of the intestinal barrier. We further discuss recent findings on functional mesenchymal heterogeneity and implications for intestinal regeneration and inflammatory intestinal pathologies.
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