疱疹病毒载体抑制由 IL-17 激活的 NF-κB 通路并促进异体间充质干细胞的成骨分化

IF 3.1 3区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Tissue Engineering and Regenerative Medicine Pub Date : 2024-08-30 DOI:10.1155/2024/8146991
Zhigang Rong, Yuhang Xi, Chengmin Zhang, Wei Dai, Hao Xue, Fei Luo, Jianzhong Xu, Fei Dai
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引用次数: 0

摘要

开发用于临床应用的组织工程骨骼(TEBs)所面临的挑战在于,源自骨髓的自体间充质干细胞(MSCs)的来源和可用性受到限制,从而形成了一个瓶颈。虽然异体间充质干细胞在 TEB 应用中大有可为,但由于移植部位的炎症反应和异体间充质干细胞引发的固有免疫反应,它们促进骨生长的能力明显减弱。因此,迫切需要开发出在移植过程中增强异体间充质干细胞成骨分化的方法。以往的研究发现,IL-17 是炎症反应早期启动炎症和级联放大的关键促炎因子,TNF-α 和 IL-17 等促炎细胞因子可抑制免疫环境中间叶干细胞的成骨分化。本研究通过病毒转染成功构建了表达HVEM的间充质干细胞,并通过体外实验和小鼠犊骨缺损(直径约3毫米)模型进一步证实了IL-17可抑制异体间充质干细胞的体内和体外成骨,而表达疱疹病毒进入介质(HVEM)的间充质干细胞具有抑制免疫反应和维持强大成骨潜能的能力。我们进一步指出,HVEM促进异体间充质干细胞成骨的机制与其抑制免疫环境中IL-17激活的IκB激酶(IKK)-NF-κB信号通路有关,它能显著抑制IKK-NF-κB通路诱导的间充质干细胞中β-catenin的泛素化和降解,上调β-catenin的表达,促进骨形成。因此,这项研究初步建立了异体间充质干细胞移植过程中Wnt/β-catenin信号通路与IKK-NF-κB通路之间的联系,为HVEM表达的间充质干细胞可能用于骨缺损的临床治疗提供了新的研究途径和理论基础。
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Herpesvirus-Entry Mediator Inhibits the NF-κB Pathway Activated by IL-17 and Fosters the Osteogenic Differentiation of Allogeneic Mesenchymal Stem Cells

The challenge in developing tissue-engineered bones (TEBs) for clinical applications lies in the constraints associated with the source and availability of autologous mesenchymal stem cells (MSCs) derived from the bone marrow, which creates a bottleneck. While allogeneic MSCs have shown promise in TEB applications, their ability to promote bone growth is notably diminished because of the inflammatory reaction at the transplant site and the inherent immune response triggered by allogeneic MSCs. Hence, there is a pressing need to develop methods that enhance the osteogenic differentiation of allogeneic MSCs during transplantation. Previous studies have found that IL-17 is a key proinflammatory factor in initiating inflammation and cascade amplification in the early stages of an inflammatory response, and proinflammatory cytokines such as TNF-α and IL-17 can inhibit the osteogenic differentiation of MSCs in an immune environment. In this study, MSCs expressing HVEM were successfully constructed by viral transfection and further reconfirmed that IL-17 can inhibit the in vivo and in vitro osteogenesis of allogeneic MSCs through in vitro experiments and mouse calvarial bone defect (diameter about 3 mm) model, while MSCs that express herpesvirus-entry mediator (HVEM) exhibit the capacity to suppress immune responses and sustain strong osteogenic potential. We further pointed out that the mechanism by which HVEM promotes the osteogenesis of allogeneic MSCs is related to its inhibition of the IκB kinase (IKK)-NF-κB signaling pathway activated by IL-17 in the immune environment, which can significantly inhibit the ubiquitination and degradation of β-catenin in MSCs induced by the IKK-NF-κB pathway, upregulate the expression of β-catenin, and promote bone formation. Hence, this research provides an initial connection between the Wnt/β-catenin signaling pathway and the IKK-NF-κB pathway during allogeneic MSC transplantation, offering new avenues for investigation and establishing a theoretical foundation for the potential use of HVEM-expressing MSCs in clinical treatments for bone defects.

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来源期刊
CiteScore
7.50
自引率
3.00%
发文量
97
审稿时长
4-8 weeks
期刊介绍: Journal of Tissue Engineering and Regenerative Medicine publishes rapidly and rigorously peer-reviewed research papers, reviews, clinical case reports, perspectives, and short communications on topics relevant to the development of therapeutic approaches which combine stem or progenitor cells, biomaterials and scaffolds, growth factors and other bioactive agents, and their respective constructs. All papers should deal with research that has a direct or potential impact on the development of novel clinical approaches for the regeneration or repair of tissues and organs. The journal is multidisciplinary, covering the combination of the principles of life sciences and engineering in efforts to advance medicine and clinical strategies. The journal focuses on the use of cells, materials, and biochemical/mechanical factors in the development of biological functional substitutes that restore, maintain, or improve tissue or organ function. The journal publishes research on any tissue or organ and covers all key aspects of the field, including the development of new biomaterials and processing of scaffolds; the use of different types of cells (mainly stem and progenitor cells) and their culture in specific bioreactors; studies in relevant animal models; and clinical trials in human patients performed under strict regulatory and ethical frameworks. Manuscripts describing the use of advanced methods for the characterization of engineered tissues are also of special interest to the journal readership.
期刊最新文献
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