Intrathecal Transplantation of Human Umbilical Cord‐Derived
MSCs
Outperforms Intravenous Administration in Attenuating Pathology and Cognitive Deficits in Alzheimer's Disease Mice
Li Ding, Wei Yu, Yuqian Chen, Hu Wang, Shuya Li, Hanyu Li, Tianyu Shu, Xiaohe Huang, Ying Yang, Rui Liu, Xinglin Liu, Zhibing Ai, Xingrong Guo, Jun Chen, Qiumin Qu ABSTRACT
Background
Mesenchymal stem cell (MSC)‐based therapies have emerged as a promising approach for Alzheimer's disease (AD), owing to their neuroprotective, anti‐inflammatory, and immunomodulatory properties. However, the optimal delivery route for maximizing therapeutic efficacy within the central nervous system remains unclear. This study aimed to directly compare the therapeutic effects of intravenous versus intrathecal transplantation of human umbilical cord‐derived mesenchymal stem cells (HUCMSCs) in a transgenic AD mouse model (5xFAD).
Methods
HUCMSCs were isolated, characterized, and administered to 5xFAD mice via intravenous or intrathecal routes. Cognitive function was assessed using the Morris water maze. Amyloid plaque burden, microglial activation, microglial barrier integrity, and axonal dystrophy were evaluated through immunofluorescence and confocal microscopy. The expression of TREM2, DAP12, and Syk was analyzed to elucidate underlying molecular mechanisms.
Results
Intrathecal transplantation of HUCMSCs significantly improved spatial learning and memory in 5xFAD mice compared to intravenous delivery. HUCMSC treatment substantially reduced amyloid plaque burden and axonal dystrophy, while promoting microglial activation and enhancing the protective function of the microglial barrier. Additionally, HUCMSC administration upregulated TREM2, DAP12, and Syk expression, with intrathecal delivery inducing more robust activation of these microglial signaling pathways than intravenous infusion.
Conclusions
HUCMSC transplantation alleviates cognitive deficits and modulates key pathological and molecular features of AD in the 5xFAD mouse model, with intrathecal administration demonstrating superior therapeutic efficacy compared to intravenous delivery. These findings underscore the critical importance of optimizing cell delivery routes to enhance the clinical potential of stem cell‐based interventions for AD.