Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-κB-dependent mechanism
Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-κB-dependent mechanism
复制标题
脯氨酰羟化酶 2 沉默通过 NF-κ B 依赖性机制增强间充质干细胞对坏死性小肠结肠炎的旁分泌作用
DOI：
10.1038/s41419-020-2378-3
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发表时间：
2020-03-16
影响因子：
9
通讯作者：
Sha, Weihong
中科院分区：
文献类型：
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作者：
Chen, Hao;Zhang, Haifeng;Sha, Weihong
坏死性小肠结肠炎（NEC）的治疗选择仍然不足。在这里，我们研究了脯氨酰羟化酶 2 (PHD2) 沉默是否以及如何增强骨髓间充质干细胞 (BM-MSC) 对 NEC 的旁分泌作用。在本研究中，用含有 GFP (GFP-MSC) 或 shPHD2-GFP 构建体 (PHDMSC) 的慢病毒转导 BM-MSC，然后将 PHDMSC 条件培养基 (PHDMSC-CM) 或 GFP-MSC 条件培养基 (MSC-CM) 腹腔注射到 NEC 幼鼠模型中。我们的结果表明，全身输注 PHDMSC-CM（而非 MSC-CM）可显着改善 NEC 大鼠的肠道损伤和存活率。这些益处可能涉及上皮再生和炎症的调节，如肠上皮/干细胞的再生、Treg 细胞功能的调节以及促炎/抗炎细胞因子平衡所示。 PHDMSC 卓越的旁分泌功效的机制与关键因子 IGF-1 和 TGF-β 2 的较高释放有关。PHD2 沉默可诱导 NF-κ B 激活，通过与 IGF-1 和 TGF-β 2 基因启动子结合诱导 IGF-1 和 TGF-β 2 分泌。我们的工作表明，PHD2 沉默通过 NF-κ B 依赖性机制增强 BM-MSC 对 NEC 的旁分泌作用，这可能是干细胞治疗 NEC 的新策略。
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.