TY - JOUR
T1 - The administration of amnion-derived multipotent cell secretome ST266 protects against necrotizing enterocolitis in mice and piglets
AU - Sodhi, Chhinder P.
AU - Ahmad, Raheel
AU - Jia, Hongpeng
AU - Fulton, William B.
AU - Lopez, Carla
AU - Gonzalez Salazar, Andres J.
AU - Ishiyama, Asuka
AU - Sampah, Maame
AU - Steinway, Steve
AU - Wang, Sanxia
AU - Prindle, Thomas
AU - Wang, Menghan
AU - Steed, David L.
AU - Wessel, Howard
AU - Kirshner, Ziv
AU - Brown, Larry R.
AU - Lu, Peng
AU - Hackam, David J.
N1 - Publisher Copyright:
Copyright © 2022 the American Physiological Society.
PY - 2022/9
Y1 - 2022/9
N2 - 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 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 epithelial cells, intestinal organoids, and human intestinal samples ex vivo, independent of epidermal growth factor. Strikingly, RNAseq analysis of the intestinal epithelium in mice reveals that 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.
AB - 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 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 epithelial cells, intestinal organoids, and human intestinal samples ex vivo, independent of epidermal growth factor. Strikingly, RNAseq analysis of the intestinal epithelium in mice reveals that 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.
KW - RNAseq
KW - Toll-like receptor 4
KW - enterocyte
KW - intestinal transcriptome
KW - necrotizing enterocolitis
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U2 - 10.1152/ajpgi.00364.2021
DO - 10.1152/ajpgi.00364.2021
M3 - Article
C2 - 35819175
AN - SCOPUS:85137125504
SN - 0193-1857
VL - 323
SP - G265-G282
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 3
ER -