An international study led by Paolo Fiorina at Boston Children’s Hospital, in collaboration with researchers from the University of Milan, has highlighted the beneficial role of inhibiting the death receptor TMEM219 in promoting mucosal healing in inflammatory bowel disease (IBD). The findings were published today in the Journal of Clinical Investigation.
Fiorina and colleagues demonstrated that blocking TMEM219 signaling through a recombinant protein based on the receptor’s extracellular domain preserves the self-renewal capacity of intestinal stem cells in IBD. This inhibition protects these stem cells from TMEM219 activation-induced cell death and prevents the progression of colitis in mouse models. The results were further validated by selective genetic suppression of TMEM219 in LGR5+ intestinal stem cells, which maintained mucosal regeneration and healing during inflammation. These findings suggest a novel disease mechanism in which TMEM219 overactivation induces intestinal stem cell death and impairs mucosal renewal during inflammatory episodes.
This newly identified signaling pathway regulates the fate and survival of intestinal stem cells. The study illustrates how dysregulated TMEM219 activity during inflammation controls mucosal self-renewal, particularly in IBD patients. In cases where patients are unresponsive to treatment or have active disease, this dysregulation of the TMEM219 axis may hinder mucosal healing and exacerbate the condition.
Paolo Fiorina, Associate Scientist in the Nephrology Department at Boston Children’s Hospital and Lecturer at Harvard Medical School, noted, “Restoring the self-renewal ability of intestinal stem cells and promoting mucosal healing during colitis is critical for IBD patients, especially those who do not respond to current therapies, experience frequent relapses, and ultimately require surgery.”
The research team’s previous studies have emphasized the role of IGFBP3/TMEM219 signaling in diabetes, particularly in insulin-producing beta cells. This latest work expands the importance of TMEM219 signaling as a novel pathogenic mechanism in colitis.
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