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bioRxiv · 10.1101/2020.10.05.327437

Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis and supports restoration of the intestinal stem cell niche

Weis, V. G.·Deal, A. C.·Mekkey, G.·Clouse, C.·Gaffley, M.·Whitaker, E.·Weis, J. A.·Schwartz, M. Z.·Atala, A.
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Abstract

Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 hours into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum was assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of Paneth cells and LGR5+ stem cells in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared to NEC littermates. Further, the intestinal stem cell niche of Paneth cells and LGR5+ stem cells was increased with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage in part through support of the intestinal stem cell niche. New and NoteworthyThese studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can now be utilized to elucidate critical neonatal repair mechanisms to overcome NEC disease.

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Weis, V. G., Deal, A. C., Mekkey, G., Clouse, C., Gaffley, M., Whitaker, E., Weis, J. A., Schwartz, M. Z., Atala, A.. 2020-10-06. Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis and supports restoration of the intestinal stem cell niche. https://doi.org/10.1101/2020.10.05.327437

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