single-cell-seeded-human-intestinal-organoids-for-organoid-research

Single Cell-Seeded Human Intestinal Organoids for Organoid Research

Recent developments in organoid technology have enabled the creation of patient-derived intestinal organoids (PDIOs) that recapitulate the structural, ...

Yonsei University College of Medicine

Tofacitinib Uptake by Patient-Derived Intestinal Organoids Predicts Individual Clinical Responsiveness.

The role of goblet cells in small intestinal inflammation in Crohn's disease (CD) is unknown. Polymorphisms of NOD2 confer risk for CD and associate with small intestinal disease location. We previously showed in mice that Nod2 deficiency leads to overexpansion of Phocaeicola vulgatus in the gut and downstream goblet cell defects, which preceded small intestinal inflammation. In this study, we ask whether goblet cell defects occur in patients with CD with NOD2 polymorphisms and investigate in mice how Pvulgatus signals through the intestinal epithelium.

Goblet Cell Loss Linked to NOD2 and Secondary Resection in Crohn's Disease Is Induced by Dysbiosis and Epithelial MyD88.

Current therapies for inflammatory bowel disease (IBD) often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects. To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton's jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3⁺ regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.

Article	Year
Tofacitinib Uptake by Patient-Derived Intestinal Organoids Predicts Individual Clinical Responsiveness. Gastroenterology\| PubMed ID: 39094749	2024
Goblet Cell Loss Linked to NOD2 and Secondary Resection in Crohn's Disease Is Induced by Dysbiosis and Epithelial MyD88. Cellular and molecular gastroenterology and hepatology\| PubMed ID: 40378921	2025
Engineered extracellular vesicles reprogram T cells by targeting PD-1 and PHB1 signaling in inflammatory bowel disease. Signal transduction and targeted therapy\| PubMed ID: 41444211	2025

Kyung Ku Jang

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