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Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-?B-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-?2. NF-?B activation was induced by PHD2 silencing to induce IGF-1 and TGF-?2 secretion via binding to IGF-1 and TGF-?2 gene promoter. Our work indicated that PHD2 silencing enhanced the paracrine effect of BM-MSCs on NEC via the NF-?B-dependent mechanism which may be a novel strategy for stem cell therapy on NEC.

SUBMITTER: Chen H

PROVIDER: S-EPMC7075868 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Chen Hao H Zhang Haifeng H Zheng Yue Y Min Xiaohui X Luo Yujun Y Zhou Weijie W Ma Faxin F Li Jinliang J Lu Quan Q Zhang Chen C Cai Huihua H Sha Weihong W Sha Weihong W

Cell death & disease 20200316 3

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 ...[more]

PMID: 32179740

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Project description:RationaleTransplantation of stem cells into damaged hearts has had modest success as a treatment for ischemic heart disease. One of the limitations is the poor stem cell survival in the diseased microenvironment. Prolyl hydroxylase domain protein 2 (PHD2) is a cellular oxygen sensor that regulates 2 key transcription factors involved in cell survival and inflammation: hypoxia-inducible factor and nuclear factor-κB.ObjectiveWe studied whether and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts.Methods and resultsADSCs were transduced with lentiviral short hairpin RNA against prolyl hydroxylase domain protein 2 (shPHD2) to silence PHD2. ADSCs, with or without shPHD2, were transplanted after myocardial infarction in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSC survival, which was abolished by short hairpin RNA against hypoxia-inducible factor-1α. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were significantly higher in the conditioned medium of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. Nuclear factor-κB activation was induced by shPHD2 to induce IGF-1 secretion via binding to IGF-1 gene promoter.ConclusionsPHD2 silencing promotes ADSCs survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. The prosurvival effect of shPHD2 on ADSCs is hypoxia-inducible factor-1α dependent, and the enhanced paracrine function of shPHD2-ADSCs is associated with nuclear factor-κB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after myocardial infarction.

Dataset Information

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

Publications

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

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