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Peer-reviewedCC BY 4.0CNS Neuroscience & Therapeutics

Intrathecal Transplantation of Human Umbilical Cord‐Derived MSCs Outperforms Intravenous Administration in Attenuating Pathology and Cognitive Deficits in Alzheimer's Disease Mice

  • Li Ding1,2
  • Wei Yu2
  • Yuqian Chen2
  • Hu Wang3
  • Shuya Li3
  • Hanyu Li3
  • Tianyu Shu2
  • Xiaohe Huang2
  • Ying Yang2
  • Rui Liu4
  • Xinglin Liu5
  • Zhibing Ai2
3 more authors
  • Xingrong Guo2
  • Jun Chen2
  • Qiumin Qu1
5 affiliations
  1. 1Department of Neurology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an China
  2. 2Department of Neurology, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Hubei Key Laboratory of Embryonic Stem Cell Research Taihe Hospital, Hubei University of Medicine Shiyan Hubei China
  3. 3Neuroregeneration and Stem Cell Programs, Department of Neurology, Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore Maryland USA
  4. 4Department of Anatomy Hubei University of Medicine Shiyan Hubei China
  5. 5Laboratory Animal Center Hubei University of Medicine Shiyan Hubei China
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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.

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Cite

BibTeXRIS
BibTeX
@article{ding2026intrathecal,
  title = {{Intrathecal Transplantation of Human Umbilical Cord‐Derived MSCs Outperforms Intravenous Administration in Attenuating Pathology and Cognitive Deficits in Alzheimer's Disease Mice}},
  author = {Li Ding and Wei Yu and Yuqian Chen and Hu Wang and Shuya Li and Hanyu Li and Tianyu Shu and Xiaohe Huang and Ying Yang and Rui Liu and Xinglin Liu and Zhibing Ai and Xingrong Guo and Jun Chen and Qiumin Qu},
  journal = {CNS Neuroscience \& Therapeutics},
  year = {2026},
  month = nov,
  doi = {10.1002/cns.71215},
  url = {https://doi.org/10.1002/cns.71215},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Intrathecal Transplantation of Human Umbilical Cord‐Derived MSCs Outperforms Intravenous Administration in Attenuating Pathology and Cognitive Deficits in Alzheimer's Disease Mice
AU  - Li Ding
AU  - Wei Yu
AU  - Yuqian Chen
AU  - Hu Wang
AU  - Shuya Li
AU  - Hanyu Li
AU  - Tianyu Shu
AU  - Xiaohe Huang
AU  - Ying Yang
AU  - Rui Liu
AU  - Xinglin Liu
AU  - Zhibing Ai
AU  - Xingrong Guo
AU  - Jun Chen
AU  - Qiumin Qu
PY  - 2026
DA  - 2026/11/04
JO  - CNS Neuroscience & Therapeutics
DO  - 10.1002/cns.71215
UR  - https://doi.org/10.1002/cns.71215
AB  - 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.
SN  - 1755-5930
SN  - 1755-5949
ER  -