The administration of amnion-derived multipotent cell secretome ST266 protects against necrotizing enterocolitis in mice and piglets

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and is steadily ris-ing in frequency. Patients who develop NEC have a very high mortality, illustrating the importance of developing novel preven-tion or treatment approaches. We and others have shown that NEC arises in part from exaggerated signaling via the bacterial receptor, Toll-like receptor 4 (TLR4) on the intestinal epithelium, leading to widespread intestinal inflammation and intestinal is-chemia. Strategies that limit the extent of TLR4 signaling, including the administration of amniotic fluid, can reduce NEC develop-ment in mouse and piglet models. We now seek to test the hypothesis that a secretome derived from amnion-derived cells can prevent or treat NEC in preclinical models of this disease via a process involving TLR4 inhibition. In support of this hypothesis, we show that the administration of this secretome, named ST266, to mice or piglets can prevent and treat experimental NEC. The protective effects of ST266 occurred in the presence of marked TLR4 inhibition in the intestinal epithelium of cultured epi-thelial cells, intestinal organoids, and human intestinal samples ex vivo, independent of epidermal growth factor. Strikingly, RNA-seq analysis of the intestinal epithelium in mice reveals that the ST266 upregulates critical genes associated with gut remodel-ing, intestinal immunity, gut differentiation. and energy metabolism. These findings show that the amnion-derived secretome ST266 can prevent and treat NEC, suggesting the possibility of novel therapeutic approaches for patients with this devastating disease.NEW & NOTEWORTHY This work provides hope for children who develop NEC, a devastating disease of premature infants that is often fatal, by revealing that the secreted product of amniotic progenitor cells (called ST266) can prevent or treat NEC in mice, piglet, and NEC-in-a-dish models of this disease. Mechanistically, ST266 prevented bacterial signaling, and a detailed transcriptomic analysis revealed effects on gut differentiation, immunity, and metabolism. Thus, an amniotic secretome may offer novel approaches for NEC.

Automated summary

This study shows that the secreted product of amniotic progenitor cells, ST266, can prevent and treat necrotizing enterocolitis (NEC) through inhibiting Toll-like receptor 4 (TLR4) signaling, and also affects important genes associated with gut remodeling, immunity, and metabolism. These findings suggest that the amniotic secretome may offer novel therapeutic approaches for NEC.