Zhao Yuan, Liu Weipeng, Ding Yabing, Zhou Jie, Zhang Fan, Wang Zhaoyan, Wang Qian, Luan Zuo
Department of Pediatrics, The Sixth Medical Center of PLA General Hospital, Beijing, China.
Department of Pediatrics, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Sci Rep. 2025 May 26;15(1):18442. doi: 10.1038/s41598-025-03563-x.
This study was designed to comprehensively elucidate the mechanism by which human umbilical cord-derived mesenchymal stem cell (hUC-MSC) therapy modulates epithelial cell apoptosis and preserves the integrity of the intestinal barrier. A series of meticulously planned in vivo and in vitro experiments were conducted to evaluate the effects of hUC-MSC treatment on various pathological parameters. Our in vivo findings demonstrated that hUC-MSC therapy significantly attenuated pathological damage, as evidenced by decreased tissue necrosis and inflammation. Furthermore, ultrastructural injury to the intestinal epithelium and mast cell infiltration were notably alleviated. With respect to the systemic immune response, serum levels of key immune factors, including IgG, IgE, mouse mast cell protease (mMCP-1), histamine, interleukin (IL)-6, and tumor necrosis factor (TNF)-α, were observably reduced following hUC-MSC treatment. At the molecular level, in jejunal tissue from food allergy mice treated with hUC-MSCs, the expression of IL-6 and TNF-α mRNA was downregulated, whereas the expression of , interferon (IFN)-γ, T-box transcription factor (T-bet) mRNA was upregulated. In vitro experiments using histamine-induced apoptosis in FHs 74 Int cells revealed that hUC-MSC therapy led to a marked decrease in the expression levels of pro-apoptotic proteins Bax, caspase-3, and cleaved caspase-3. Concurrently, significant upregulation of both the anti-apoptotic protein Bcl-2 and tight junction protein Zonula Occludens-1 (ZO-1) was observed. hUC-MSCs substantially improved cellular viability during histamine challenge by suppressing apoptosis (quantified by Annexin V/7-AAD staining) and reducing reactive oxygen species (ROS) generation in FHs 74 Int cells, demonstrating dual cytoprotective effects against histamine-induced toxicity. Our findings provide compelling evidence that hUC-MSCs mediate anti-apoptotic effects via modulation of the Bax/Bcl-2 pathway in histamine-stimulated intestinal mucosa during allergic responses. These results reveal novel therapeutic potential for hUC-MSCs in maintaining epithelial homeostasis and intestinal barrier function in food allergy-associated enteritis, suggesting promising clinical applications for this disorder.
本研究旨在全面阐明人脐带间充质干细胞（hUC-MSC）治疗调节上皮细胞凋亡并维持肠道屏障完整性的机制。进行了一系列精心设计的体内和体外实验，以评估hUC-MSC治疗对各种病理参数的影响。我们的体内研究结果表明，hUC-MSC治疗显著减轻了病理损伤，组织坏死和炎症减少即为证据。此外，肠道上皮的超微结构损伤和肥大细胞浸润明显减轻。关于全身免疫反应，hUC-MSC治疗后，关键免疫因子的血清水平，包括IgG、IgE、小鼠肥大细胞蛋白酶（mMCP-1）、组胺、白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α，明显降低。在分子水平上，在用hUC-MSCs治疗的食物过敏小鼠的空肠组织中，IL-6和TNF-α mRNA的表达下调，而干扰素（IFN）-γ、T盒转录因子（T-bet）mRNA的表达上调。使用组胺诱导FHs 74 Int细胞凋亡的体外实验表明，hUC-MSC治疗导致促凋亡蛋白Bax、caspase-3和裂解的caspase-3的表达水平显著降低。同时，观察到抗凋亡蛋白Bcl-2和紧密连接蛋白闭合蛋白-1（ZO-1）均显著上调。hUC-MSCs通过抑制凋亡（通过膜联蛋白V/7-氨基放线菌素D染色定量）和减少FHs 74 Int细胞中活性氧（ROS）的产生，在组胺攻击期间显著提高了细胞活力，证明了对组胺诱导的毒性具有双重细胞保护作用。我们的研究结果提供了令人信服的证据，表明hUC-MSCs在过敏反应期间通过调节组胺刺激的肠黏膜中的Bax/Bcl-2途径介导抗凋亡作用。这些结果揭示了hUC-MSCs在维持食物过敏相关性肠炎中的上皮稳态和肠道屏障功能方面的新治疗潜力，表明该疾病具有广阔的临床应用前景。
Cells. 2021-7-8
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