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World J Stem Cells. Oct 26, 2026; 18(10): 124640
Published online Oct 26, 2026. doi: 10.4252/wjsc.124640
Human bone marrow-derived mesenchymal stem cells alleviate fluoxetine-resistant depression-like behaviors in mice by multi-target effects in the hippocampus
Yu Liu, Jian-Fei Wu, Mao-Ya Xu, Ji Kang, An-Hong Ye, Bo Liu, Ke-Zhi Liu
Yu Liu, Jian-Fei Wu, Mao-Ya Xu, Ji Kang, An-Hong Ye, Bo Liu, Ke-Zhi Liu, Center for Psychiatry Research, Zigong Mental Health Center, Zigong 643020, Sichuan Province, China
Yu Liu, Jian-Fei Wu, Mao-Ya Xu, Ji Kang, An-Hong Ye, Bo Liu, Ke-Zhi Liu, Department of Psychiatry, School of Mental Health, Southwest Medical University, Zigong 643020, Sichuan Province, China
Yu Liu, Jian-Fei Wu, Mao-Ya Xu, Ji Kang, An-Hong Ye, Bo Liu, Ke-Zhi Liu, Center for Psychiatry Research, The Zigong Institute of Brain Science, Zigong 643020, Sichuan Province, China
Ke-Zhi Liu, Psychosomatic Medicine Center, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
Co-first authors: Yu Liu and Jian-Fei Wu.
Co-corresponding authors: Bo Liu and Ke-Zhi Liu.
Author contributions: Liu Y and Wu JF contributed equally to this manuscript and are co-first authors; Liu B and Liu KZ designed the research study, they contributed equally to this manuscript and are co-corresponding authors; Liu Y, Wu JF, and Xu MY performed the research; Liu Y, Wu JF, and Liu B wrote the original manuscript; Kang J and Ye AH reviewed the manuscript.
AI contribution statement: No AI tool was used to generate research data, interpret results, or formulate conclusions.
Supported by Zigong Key Science and Technology Plan (Collaborative Innovation Project of Zigong Institute of Brain Sciences), No. 2024-NKY-01-04, No. 2025NKY0104, No. 2025NKY0201, and No. 2025NKY0105; Health Commission of Zigong High-Level Talent Development Project, No. WJW-GCCRC025; Collaborative Innovation Project of Zigong Integrated Traditional Chinese and Western Medicine Research Institute, No. 2025ZXY0206; and Health Commission of Sichuan Province Medical Science and Technology Program, No. 25QNMP018.
Institutional animal care and use committee statement: All animal research procedures were performed in accordance with the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals. The study protocol was ethically reviewed and approved by the Zigong Mental Health Center Animal Ethics Committee (Approval No. ZPRC-20250223).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Bo Liu, PhD, Center for Psychiatry Research, Zigong Mental Health Center, No. 666 Gongshu Road, Gongjing District, Zigong 643020, Sichuan Province, China.
liubo2511@163.com
Received: June 23, 2026
Revised: July 19, 2026
Accepted: October 14, 2026
Published online: October 26, 2026
Processing time: 125 Days and 17.6 Hours
BACKGROUND
Treatment-resistant depression (TRD) remains a major clinical challenge due to the limited efficacy of conventional first-line antidepressants. Mesenchymal stem cells (MSCs), which possess potent immunomodulatory and neurotrophic properties, have emerged as promising therapeutic candidates for neuropsychiatric disorders. Human bone marrow-derived MSCs (hBMSCs) are one of the most widely used sources. However, their therapeutic potential and their underlying mechanisms in the context of TRD have yet to be fully elucidated.
AIM
To investigate the antidepressant effects of hBMSCs in a TRD-like mouse model and to explore the potential molecular mechanisms involved.
METHODS
A mouse model of fluoxetine-resistant depression (FRD), defined as an early stage of TRD, was established by combining chronic unpredictable restraint stress with corticosterone administration and validated by the lack of behavioral response to fluoxetine (FLX). hBMSCs (2 × 106 cells) were administered via the tail vein twice weekly for 4 weeks. A battery of behavioral tests was conducted to evaluate depressive- and anxiety-like behaviors. Immunofluorescence staining and western blotting were performed to assess microglial activation, astrocytic integrity, neuronal survival, and hippocampal neurogenesis.
RESULTS
hBMSC treatment significantly ameliorated depressive- and anxiety-like behaviors in FRD model mice, whereas FLX failed to produce comparable behavioral improvements. hBMSCs markedly attenuated microglial activation and reduced neuroinflammatory responses in the hippocampus. In addition, hBMSCs restored astrocytic structure, protected neuronal integrity, and promoted adult hippocampal neurogenesis. These neuroprotective effects were associated with the brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element-binding signaling pathway. hBMSCs labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate were not detected in brain tissue, suggesting that their therapeutic effects may primarily rely on indirect or paracrine mechanisms.
CONCLUSION
hBMSCs exert robust antidepressant-like effects in an FRD mouse model by reducing neuroinflammation, restoring glial function, enhancing neurogenesis, and activating neurotrophic signaling, supporting hBMSCs as a promising therapy for FRD.
Core Tip: We established a mouse model of fluoxetine-resistant depression (FRD) by combining chronic unpredictable restraint stress with corticosterone administration. Systemic administration of human bone marrow-derived mesenchymal stem cells (hBMSCs) exerted robust antidepressant-like effects through multiple mechanisms, including suppression of hippocampal neuroinflammation, restoration of astrocytic integrity, protection of neuronal survival, and promotion of adult neurogenesis. These effects were associated with reactivation of the brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element-binding signaling pathway. hBMSCs did not engraft in the brain, suggesting paracrine-mediated actions. Our findings support the use of hBMSCs as a promising multi-target therapeutic strategy for FRD, an early stage of treatment-resistant depression.
