Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Cognitive Decline by Restoring Senescent Microglial Function via NF ‐ κB ‐ SREBP1 Pathway Inhibition

作者：Aihong Liang, Li Zhang, Jing Peng, Yanan Li, Yunduo Zhou, Chao Yang, Jie Wang, Yizhong Yan, Hua Mei, Jun Zhu, Siqi Wang, Na Xiao, Yu Zhou, Lamei Cheng · 发表于：Aging Cell · 年份：2025 · DOI：10.1111/acel.70259 · 被引用次数：3 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer、Neurogenesis and neuroplasticity mechanisms

Aging is a major risk factor for neurodegenerative diseases, yet the role of senescent microglia in age-related cognitive dysfunction remains incompletely understood. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We also elucidated a novel mechanism by which hUC-MSCs alleviate age-related cognitive decline by targeting senescent microglia. Specifically, we showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons. These findings highlight the therapeutic potential of hUC-MSCs in age-related neurodegenerative disorders.