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.

坏死性小肠结肠炎（NEC）的治疗选择仍然不足。在这里，我们检查了脯氨酰羟化酶2（PHD2）沉默以及如何增强NEC的骨髓间充质干细胞（BM-MSC）的旁分泌作用。在这项研究中，用含有GFP（GFP-MSC）或shPHD2-GFP构建体（PHDMSC）的慢病毒转导BM-MSC，然后腹膜内注射PHDMSC条件培养基（PHDMSC-CM）或GFP-MSC条件培养基（MSC-CM）制成NEC的大鼠幼仔模型。我们的结果表明，PHDMSC-CM的全身输注，而非MSC-CM的输注，显着改善了NEC大鼠的肠损伤和存活率。如肠道上皮/干细胞的再生所示，这种益处可能涉及上皮再生和炎症的调节，Treg细胞功能的调节和促炎/抗炎细胞因子的平衡。PHDMSC具有优异的旁分泌功效的机制与枢转因子IGF-1和TGF-β2的更高释放有关。PHD2沉默诱导NF-κB活化，通过与IGF-1和TGF-β2基因启动子结合而诱导IGF-1和TGF-β2分泌。我们的工作表明，PHD2沉默通过NF-κB依赖性机制增强了BM-MSC对NEC的旁分泌作用，这可能是NEC干细胞治疗的一种新策略。