Yasumura Yuyo, Teshima Takahiro, Nagashima Tomokazu, Michishita Masaki, Taira Yoshiaki, Suzuki Ryohei, Matsumoto Hirotaka
Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan.
Research Center for Animal Life Science, Nippon Veterinary and Life Science University, Musashino, Japan.
Front Vet Sci. 2024 Aug 8;11:1437648. doi: 10.3389/fvets.2024.1437648. eCollection 2024.
The therapeutic efficacy of mesenchymal stromal cells (MSCs) in inflammatory bowel disease is not completely known and is not consistent. Priming with inflammatory cytokines has been proposed to adapt MSCs to an inflammatory environment to have them ready to counteract it, but may have undesirable effects on MSCs, such as increased immunogenicity. In this study, we hypothesized that priming MSCs with inflamed intestinal tissue would more effectively enhance their therapeutic effect on intestinal inflammation.
The capacity of canine adipose-derived MSCs (cADSCs) primed with colon tissue homogenates from mice with experimentally induced colitis or a combination of tumor necrosis factor-α and interferon-γ to inhibit T-cell proliferation was analyzed, along with their own apoptosis, proliferation, cell surface marker expression, and transcriptome. In addition, colitis mice were treated with the primed cADSCs to assess colitis severity and immune cell profile.
Priming with cytokines induced apoptosis, decreased cell proliferation, and major histocompatibility complex-II gene expression in cADSCs, but these adverse effects were mild or absent with colitis-tissue priming. cADSCs primed with colitis tissue reduced the severity of colitis via the induction of M2 macrophages and T-regulatory cells and suppression of T-helper (Th)1/Th17-cell responses, and their effects were comparable to those of cytokine-primed cells.
Our results emphasize the importance of the activation of MSCs by the appropriate microenvironment to maximize their therapeutic effect.
间充质基质细胞（MSCs）在炎症性肠病中的治疗效果尚未完全明确且不一致。有人提出用炎性细胞因子预处理MSCs，使其适应炎症环境以对抗炎症，但这可能对MSCs产生不良影响，如增加免疫原性。在本研究中，我们假设用炎症肠道组织预处理MSCs能更有效地增强其对肠道炎症的治疗效果。
分析用实验性诱导结肠炎小鼠的结肠组织匀浆或肿瘤坏死因子-α与干扰素-γ的组合预处理的犬脂肪来源的间充质基质细胞（cADSCs）抑制T细胞增殖的能力，以及它们自身的凋亡、增殖、细胞表面标志物表达和转录组。此外，用预处理的cADSCs治疗结肠炎小鼠，以评估结肠炎严重程度和免疫细胞谱。
用细胞因子预处理诱导cADSCs凋亡、降低细胞增殖并降低主要组织相容性复合体-II基因表达，但结肠炎组织预处理时这些不良反应轻微或不存在。用结肠炎组织预处理的cADSCs通过诱导M2巨噬细胞和调节性T细胞以及抑制辅助性T（Th）1/Th17细胞反应来减轻结肠炎的严重程度，其效果与细胞因子预处理的细胞相当。
我们的结果强调了适当的微环境激活MSCs以最大化其治疗效果的重要性。
