Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-κB-dependent mechanism

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-beta 2. NF-kappa B activation was induced by PHD2 silencing to induce IGF-1 and TGF-beta 2 secretion via binding to IGF-1 and TGF-beta 2 gene promoter. Our work indicated that PHD2 silencing enhanced the paracrine effect of BM-MSCs on NEC via the NF-kappa B-dependent mechanism which may be a novel strategy for stem cell therapy on NEC.