TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis

• DOI: 10.1172/jci185783
• Publication Date: 2025-05-14T18:00:41Z
• Authors: Francesca D’Addio; Giovanni Amabile; Emma Assi; Anna Maestroni; Adriana Petrazzuolo; Cristian Loretelli; Ahmed Abdelasalam; Moufida Ben Nasr; Ida Pastore; Maria Elena Lunati; Vera Usuelli; Monica Zocchi; Andy Joe Seelam; Domenico Corradi; Stefano La Rosa; Virna Marin; Monique Zangarini; Marta Nardini; Stefano Porzio; Filippo Canducci; Claudia Nardini; Basset El Essawy; Manuela Nebuloni; Jun Yang; Massimo Venturini; Giovanni Maconi; Franco Folli; Silvio Danese; Gianvincenzo Zucc...; Gianluca M. Sampi...; Sandro Ardizzone; Paolo Fiorina

Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect now emerging. Herein, we report abnormal ISC death that occurs Crohn's disease, exacerbates colitis, limits ISC-dependent repair, controlled through the factor Transmembrane protein 219 (TMEM219). Large alterations TMEM219 expression were observed patients with particularly those active and/or who nonresponders to conventional therapy, confirming signaling abnormally activated leads failure of regenerative response. Mechanistic studies revealed proapoptotic TMEM219-mediated molecular signature associates Caspase-8 activation death. Pharmacological blockade IGFBP3/TMEM219 binding/signal recombinant ecto-TMEM219 restored self-renewal abilities miniguts generated from vitro ameliorated DSS-induced T cell-mediated colitis vivo, ultimately leading healing. Genetic tissue-specific deletion ISCs newly TMEM219fl/flLGR5cre mice revived their both vivo. Our findings demonstrate TMEM219-dependent reestablishes properties IBD.