Harnessing dental stem cell-derived synovial cells for IBD therapy: dual modulation of gut immunity and crypt repair.

Abstract

Inflammatory bowel disease (IBD) remains a therapeutic challenge due to its chronic relapsing nature and limited long-term remission strategies. Here, we propose a therapy using stem cells from human exfoliated deciduous teeth (SHEDs). We evaluated SHEDs in murine colitis models (DSS/TNBS) and human IBD tissues. Single-cell RNA sequencing (scRNA-seq) and organoid cocultures were used to characterise SHED differentiation and therapeutic mechanisms. SHEDs migrate to inflamed intestines, differentiate into TGM2⁺TFPI2⁺ quiescent fibroblast-like synovial cells (QFLSs) via a β-catenin-independent Wnt/JNK pathway, and significantly ameliorate colitis in preclinical models. Mechanistically, QFLSs exhibit dual therapeutic actions: (1) IL-6 secretion promoted Paneth cell proliferation to restore crypt homoeostasis; and (2) LIF-driven expansion of immunosuppressive Treg cells reshaped the inflammatory microenvironment. Crucially, we validated the presence of QFLSs in human IBD tissues, where their abundance correlated with reduced disease severity and improved prognosis. Our study identified SHED-derived QFLSs as multifunctional mediators that concurrently addressed epithelial damage and immune dysregulation in IBD. This cell-based strategy overcame spatial limitations of traditional therapies by leveraging endogenous repair pathways, offering a translatable blueprint for chronic inflammatory diseases. Supported by Beijing Natural Science Foundation (7242034, 7242092, L232077), National Natural Science Foundation of China (81870393, 81970500, 82473154, 81970500, and 82203559), and Jiangsu Province Basic Research Special Fund (BK20240117).