Galera Marina Ramírez, Hu Tu, Harth Lisa, Bronze Mariana, Munthe-Fog Lea, Svalgaard Jesper, Woetmann Anders
The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Center for Vaccine Research, Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
Stem Cell Rev Rep. 2025 Jun 5. doi: 10.1007/s12015-025-10906-8.
Human adipose-derived mesenchymal stromal cells (AD-MSCs) are known for their immunomodulatory responses to inflammation, a key trait for their therapeutic use in tissue injury and chronic inflammatory diseases. However, the effects of constant inflammation on their transcriptomic profile, proliferative capacity, and immunosuppressive potential remain largely unexplored. To investigate this, we evaluated the in vitro response of human AD-MSCs from three donors expanded across seven passages under, non-inflamed (DMEM), acute (IFNγ-24 h) and constant (IFNγ-C) inflammatory conditions. Bulk RNA-sequencing results demonstrated that AD-MSCs respond significantly to inflammatory stimuli. Both acute and constant inflammation induced extensive transcriptomic alterations, with differentially expressed genes related to cell cycle regulation, DNA replication, metabolism, and immunomodulation. Notably, constant inflammation was associated with a transcriptomic shift toward oxidative phosphorylation (OXPHOS). Moreover, microscopy analysis revealed a significant reduction in AD-MSCs proliferative capacity under constant inflammation, as evidenced by lower cumulative population doubling and the appearance of senescence-like morphological changes in early passages when compared to non-inflamed (DMEM) and acute inflammatory (IFNγ-24 h) conditions. Despite proliferation being impaired, co-culture assays with PBMCs demonstrated that under constant inflammation AD-MSCs immunosuppressive potential was maintained in early and late passages. Therefore, our results provide novel insights into the dual effects of constant inflammation on AD-MSCs, impairing cell proliferation while maintaining their immunosuppressive capacity. Understanding AD-MSCs' behaviour in chronically inflamed microenvironments is essential for optimizing AD-MSCs' clinical applications.
人脂肪来源的间充质基质细胞（AD-MSCs）因其对炎症的免疫调节反应而闻名，这是其在组织损伤和慢性炎症性疾病治疗应用中的关键特性。然而，持续炎症对其转录组谱、增殖能力和免疫抑制潜力的影响在很大程度上仍未得到探索。为了研究这一点，我们评估了来自三名供体的人AD-MSCs在非炎症（DMEM）、急性（IFNγ-24小时）和持续（IFNγ-C）炎症条件下传代培养七代后的体外反应。大量RNA测序结果表明，AD-MSCs对炎症刺激有显著反应。急性和持续炎症均诱导了广泛的转录组改变，差异表达基因与细胞周期调控、DNA复制、代谢和免疫调节有关。值得注意的是，持续炎症与转录组向氧化磷酸化（OXPHOS）的转变有关。此外，显微镜分析显示，与非炎症（DMEM）和急性炎症（IFNγ-24小时）条件相比，持续炎症下AD-MSCs的增殖能力显著降低，早期传代时累积群体倍增较低以及出现衰老样形态变化就是证明。尽管增殖受到损害，但与外周血单核细胞（PBMCs）的共培养试验表明，在持续炎症下，AD-MSCs在早期和晚期传代时的免疫抑制潜力得以维持。因此，我们的结果为持续炎症对AD-MSCs的双重作用提供了新的见解，即损害细胞增殖同时维持其免疫抑制能力。了解AD-MSCs在慢性炎症微环境中的行为对于优化AD-MSCs的临床应用至关重要。
