The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage.

IF 4.5 3区 医学 Q2 IMMUNOLOGY European Journal of Immunology Pub Date : 2024-11-06 DOI:10.1002/eji.202451205
Hazel Dunbar, Ian J Hawthorne, Courteney Tunstead, Molly Dunlop, Evelina Volkova, Daniel J Weiss, Claudia C Dos Santos, Michelle E Armstrong, Seamas C Donnelly, Karen English
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Abstract

Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.

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MIF 许可的间充质基质细胞在室尘螨诱导的上皮损伤中的血管内皮生长因子介导的细胞保护能力
通过使用促炎细胞因子来增强间充质基质细胞(MSC)的疗效现已得到公认。我们之前已经证明,巨噬细胞迁移抑制因子(MIF)许可的间充质干细胞在减少由屋尘螨(HDM)引起的过敏性哮喘的炎症方面的疗效显著增强。间充质干细胞分泌组释放的可溶性介质具有与细胞本身相关的细胞保护特性。在哮喘中,吸入过敏原(如 HDM)造成的上皮屏障损伤会促使鹅口疮细胞增生。血管内皮生长因子(VEGF)在修复和维持气道上皮完整性方面发挥着关键作用。人骨髓间充质干细胞表达 MIF 受体 CD74、CXCR2 和 CXCR4。来自高MIF表达CATT7骨髓源巨噬细胞的内源性MIF通过MIF CXCR4趋化因子受体增加了间充质干细胞产生的血管内皮生长因子,而用CXCR4抑制剂预孵育可减轻这种效应。CATT7-MIF 许可的间充质干细胞条件培养基含有更高水平的血管内皮生长因子,可通过体外迁移和增殖显著促进支气管上皮伤口愈合。阻断血管内皮生长因子受体 2 或使用丝裂霉素 C 可消除这种效应。此外,CATT7-MIF 间充质干细胞 CM 能明显减少体内 HDM 挑战后的鹅口疮细胞增生。由于使用抗人血管内皮生长因子中和抗体可消除这种效应,因此证实了这种效应是血管内皮生长因子依赖性的。总之,这项研究强调,MIF 授权的间充质干细胞能增强血管内皮生长因子的产生,从而有能力修复肺上皮细胞。
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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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