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      Leukemia Inhibitory Factor Facilitates Self-Renewal and Differentiation and Attenuates Oxidative Stress of BMSCs by Activating PI3K/AKT Signaling

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          Abstract

          Objective

          Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) remains a hopeful therapeutic approach for bone defect reconstruction. Herein, we investigated the effects and mechanisms of leukemia inhibitory factor (LIF) in the function and viability of hypoxic BMSCs as well as bone defect repair.

          Methods

          The effects of LIF on apoptosis (flow cytometry, TUNEL staining), mitochondrial activity (JC-1 staining), proliferation (colony formation, EdU staining), and differentiation (CD105, CD90, and CD29 via flow sorting) were examined in hypoxic BMSCs. LIF, LIFR, gp130, Keap1, Nrf2, antioxidant enzymes (SOD1, catalase, GPx-3), bone-specific matrix proteins (ALP, BSP, OCN), PI3K, and Akt were detected via immunoblotting or immunofluorescent staining. BMSCs combined with biphasic calcium phosphate scaffolds were implanted into calvarial bone defect mice, and the therapeutic effect of LIF on bone defect was investigated.

          Results

          Hypoxic BMSCs had increased apoptosis and oxidative stress and reduced mitochondrial activity. Additionally, LIF, LIFR, and gp130 were upregulated and PI3K/Akt activity was depressed in hypoxic BMSCs. Upregulated LIF alleviated apoptosis and oxidative stress and heightened mitochondrial activity and PI3K/Akt signaling in hypoxic BMSCs. Additionally, LIF overexpression promoted self-renewal and osteogenic differentiation of BMSCs with hypoxic condition. Mechanically, LIF facilitated self-renewal and differentiation as well as attenuated oxidative stress of BMSCs through enhancing PI3K/AKT signaling activity. Implantation of LIF-overexpressed BMSC-loaded BCP scaffolds promoted osteogenesis as well as alleviated oxidative stress and apoptosis through PI3K/Akt signaling.

          Conclusion

          Our findings demonstrate that LIF facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by PI3K/AKT signaling.

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          Most cited references37

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          IL-6 as a keystone cytokine in health and disease.

          Christopher A. Hunter, Simon A. Jones (2015)
          Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
          Article 0 comments Cited 525 times – based on 0 reviews     Review now
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            NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases

            Min Woo Park, Hyeon Woo Cha, Junhyung Kim … (2021)
            Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.
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              Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation.

              Seungha Hyeon, Hyojung Lee, Yoohee Yang … (2013)
              Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of a variety of antioxidant and detoxification genes through an antioxidant-response element. Nrf2 has been shown to protect several types of cells against the acute and chronic injury that accompanies oxidative stress, but its role in osteoclasts remains unclear. In this study, we investigated the role of Nrf2 in osteoclast (OC) differentiation, a process in which reactive oxygen species (ROS) are generated and then participate, using Nrf2-knockout mice. Receptor activator of nuclear factor κB ligand (RANKL)-induced OC differentiation, actin ring formation, and osteoclastic bone resorption were substantially promoted in Nrf2-deficient OC precursor cells compared to wild-type cells. Under both unstimulated and RANKL-stimulated conditions, Nrf2 loss led to an increase in the intracellular ROS level and the oxidized-to-reduced glutathione ratio and a defect in the production of numerous antioxidant enzymes and glutathione. Moreover, pretreatment with N-acetylcysteine or diphenyleneiodonium significantly reduced the OC differentiation and decreased the intracellular ROS level in both Nrf2-deficient and wild-type cells. Pretreatment with sulforaphane and curcumin also inhibited the OC differentiation by activating Nrf2 in part. Nrf2 deficiency promoted the RANKL-induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; the induction of c-Fos; and the consequent induction of nuclear factor of activated T cells, cytoplasmic 1, a pivotal determinant of OC differentiation. Our results suggest that Nrf2 probably inhibits RANKL-induced OC differentiation by regulating the cellular redox status by controlling the expression of oxidative response genes, findings that might form the basis of a new strategy for treating inflammatory bone diseases. © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Youde Liang:
                ORCID: https://orcid.org/0000-0002-8825-7323
                Xiangxiang Zhao:
                ORCID: https://orcid.org/0000-0002-3546-437X
                Journal
                Journal ID (nlm-ta): Oxid Med Cell Longev
                Journal ID (iso-abbrev): Oxid Med Cell Longev
                Journal ID (publisher-id): OMCL
                Title: Oxidative Medicine and Cellular Longevity
                Publisher: Hindawi
                ISSN (Print): 1942-0900
                ISSN (Electronic): 1942-0994
                Publication date Collection: 2022
                Publication date (Electronic): 5 September 2022
                Volume: 2022
                Electronic Location Identifier: 5772509
                Affiliations
                1Department of Stomatology, Southern University of Science and Technology Yantian Hospital, Shenzhen, Guangdong, China
                2Department of Neurology, Changhai Hospital, Naval Medical University, Shanghai, China
                Author notes

                Academic Editor: Tian Li

                Author information
                https://orcid.org/0000-0002-8825-7323
                https://orcid.org/0000-0002-6470-4950
                https://orcid.org/0000-0002-3546-437X
                Article
                DOI: 10.1155/2022/5772509
                PMC ID: 9467750
                PubMed ID: 36105481
                SO-VID: cde54ca7-ae26-43d2-b914-eec20b62c342
                Copyright © Copyright © 2022 Youde Liang et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 2 May 2022
                Date revision received : 9 July 2022
                Date accepted : 15 July 2022
                Funding
                Funded by: Project of Yantian District in Shenzhen City
                Award ID: 20190106
                Funded by: Shenzhen Science and Technology Innovative Project
                Award ID: JCYJ20180302144621755
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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