Abstract
Treatment options for necrotizing enterocolitis (NEC) remain inadequate. Here we examined if and how prolyl hydroxylase 2 (PHD2) silencing enhances the paracrine effects of bone-marrow-derived mesenchymal stem cells (BM-MSCs) on NEC. In this study, BM-MSCs were transduced with lentiviruses containing GFP (GFP-MSC) or shPHD2-GFP constructs (PHDMSC), followed by intraperitoneal injection of the PHDMSC-conditioned medium (PHDMSC-CM) or the GFP-MSC-conditioned medium (MSC-CM) into a rat pup model of NEC. Our results showed that systemic infusion of PHDMSC-CM, but not MSC-CM, significantly improved intestinal damage and survival of NEC rats. Such benefits may involve the modulation of epithelial regeneration and inflammation, as indicated by the regeneration of intestinal epithelial/stem cells, the regulation of Treg cells function and pro-/anti-inflammatory cytokine balance. The mechanism for the superior paracrine efficacy of PHDMSC is related to a higher release of pivotal factor IGF-1 and TGF-β2. NF-κB activation was induced by PHD2 silencing to induce IGF-1 and TGF-β2 secretion via binding to IGF-1 and TGF-β2 gene promoter. Our work indicated that PHD2 silencing enhanced the paracrine effect of BM-MSCs on NEC via the NF-κB-dependent mechanism which may be a novel strategy for stem cell therapy on NEC.
Highlights
Necrotizing enterocolitis (NEC) is the most common acute gastrointestinal illness in newborns, occurring in 7–10% of premature infants with a mortality rate of 20–50%1
Since vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), IGF-1, TGF-β1, and TGF-β2 were significantly elevated after prolyl hydroxylase 2 (PHD2) silencing, and previous studies had suggested that these cytokines played an active role in NEC repair[20,22,23], we further studied if the beneficial effect of PHD2 expression in MSCs (PHDMSC)-CM on NEC was associated with these cytokines
PHD2 silencing enhances the paracrine efficacy of BMMSCs on NEC, and demonstrated that PHDMSC-CM, but not mesenchymal stem cells (MSCs)-conditioned medium (MSC-CM), (1) improves survival and promotes the structural and functional restoration of NEC by regulating epithelial regeneration and inflammatory response; (2) activates nuclear factor-κB (NF-κB) to increase their secretion of pivotal factor IGF-1 and TGF-β2 via binding to IGF-1 and TGFβ2 gene promoter, provides superior therapeutic efficacy on NEC
Summary
Necrotizing enterocolitis (NEC) is the most common acute gastrointestinal illness in newborns, occurring in 7–10% of premature infants with a mortality rate of 20–50%1. The etiology and pathophysiology of NEC remain unclear, treatment options for infants affected by NEC are limited to supportive care, with twenty to forty. NEC research has been conducted for decades, this disease remains the leading cause of morbidity and mortality in preterm infants[3]. Stem cell therapy may be one of the most promising treatments for NEC. The abilities of stem cells to inhibit inflammation and tissue repair have aroused great interest for the treatment of NEC4. Stem cells have been reported to repair different types of small intestinal injuries[5,6,7]. The reparative effect of stem cells is manifested in stem cell migration and implantation into damaged tissues, but more importantly, stem cells secrete a variety of trophic mediators, such as growth factors, immunomodulatory factors, and RNA-containing
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