GSE193177
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 rising in frequency. Patients who develop NEC have a very high mortality, illustrating the importance of developing novel prevention 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 ischemia. Strategies that limit the extent of TLR4 signaling, including the administration of amniotic fluid, can reduce NEC development 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 pre-clinical 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. We further show that the protective effects of ST266 occurred in the presence of marked TLR4 inhibition in the intestinal epithelium of cultured epithelial cells, intestinal organoids, and human intestinal samples ex vivo. Strikingly, RNA-seq analysis of the intestinal epithelium in mice reveal the ST266 upregulates critical genes associated with gut remodeling, 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. Overall design: For RNAseq analysis, 16 samples from four experimental groups were collected from mouse ileum at age p11 with four replicates. Group 1: Breastfed control mice; Group 2: Mice with experimental NEC; Group 3: Mice with experimental NEC administered ST266 orally; Group 4: Mice with experimental NEC administered ST266 intraperitoneally.