Neuroprotective effect of mesenchymal stem cell-derived miR-143-3p on dopaminergic neurons via the TLR3/NF-κB/p53 signaling pathway
6 affiliations
- 1State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University
- 2Laboratory for Regenerative Cell Therapy, Department of Neurosurgery, Massachusetts General Hospital, George A. ‘‘Doc’’ Lopez, Harvard Medical School
- 3Department of Neurosurgery, Huashan Hospital, Fudan University
- 4State Key Laboratory of Brain Function and Disorders, Department of Neurology and National Research Center for Aging and Medicine, National Center for Neurological Disorders, Huashan Hospital, Fudan University
- 5Department of Molecular Medicine, School of Bio-Pharmaceutical Convergence, Institute for Precision Therapeutics, Hanyang University
- 6Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University
Abstract
Background Transplantation of midbrain dopaminergic neurons (mDANs) derived from human pluripotent stem cells (hPSCs) represents a promising therapeutic approach for Parkinson’s disease (PD), with several clinical trials currently in progress. However, the poor survival of grafted mDANs, in part due to inflammation triggered by surgical injury, poses significant challenges to both therapeutic efficacy and safety. In recent years, mesenchymal stem cells (MSCs) and their derivatives have played an important role in the field of stem cell therapy due to their easy accessibility and immunomodulatory properties. However, their potential role as an adjunct in cell therapy remains unclear. Therefore, this study aims to investigate the protective effects of conditioned medium (CM) derived from MSCs and the mechanisms of action by which it attenuates surgery-induced neuroinflammation and enhances the survival of transplanted mDANs. Methods To mimic the neuroinflammatory response caused by the surgical aspect of cell transplantation, transplantation medium alone (i.e. without cells) was injected into the striatum of male NOD SCID mice. The anti-inflammatory effects of MSC-CM in vivo were evaluated by assessing the activation of microglia and expression levels of pro-inflammatory cytokines. Next, an in vitro cell death model was established using IFN-γ and TNF-α stimulation. The protective effects of MSC-CM against IFN-γ and TNF-α-induced inflammatory injury in mDANs were assessed using immunofluorescence staining and TUNEL assay. To identify the active components and underlying mechanisms for the protective effects of MSC-CM, inhibitory treatments, miRNA sequencing, dual-luciferase reporter assay, and subsequent validation by qPCR and Western blotting were performed. Finally, MSC-CM was administered intranasally into male NOD SCID mice following mDAN transplantation to evaluate its protective effects on the grafted mDANs in vivo. Results MSC-CM suppressed neuroinflammation and significantly protected mDANs from inflammation-induced cell death via inhibition of TLR3/NF-κB/p53 signaling pathway in this model system. This protective effect was largely reproduced by treatment with a specific component of the MSC-CM, miR-143-3p. Overexpression of miR-143-3p further enhanced the protective effects and mechanisms of action of MSC-CM. Conclusions This study demonstrates that MSC-CM or its component miR-143-3p exert protective effects on mDANs against inflammatory injury, primarily by inhibiting the TLR3/NFκB/p53 signaling pathway.
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BibTeX
@article{sun2026neuroprotective,
title = {{Neuroprotective effect of mesenchymal stem cell-derived miR-143-3p on dopaminergic neurons via the TLR3/NF-κB/p53 signaling pathway}},
author = {Jing Sun and Tian Wang and Chen Qiu and Tianwen Li and Peng Wang and Tatyana Matveeva and Tanner Boyd and Qingyuan Tang and Jun Xue and Lu Su and Hyemyung Seo and Yi Eve Sun and Tian-Lin Cheng and Jeffrey Schweitzer and Bin Song},
journal = {Stem Cell Research \& Therapy},
year = {2026},
month = jul,
doi = {10.1186/s13287-026-05186-z},
url = {https://doi.org/10.1186/s13287-026-05186-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neuroprotective effect of mesenchymal stem cell-derived miR-143-3p on dopaminergic neurons via the TLR3/NF-κB/p53 signaling pathway
AU - Jing Sun
AU - Tian Wang
AU - Chen Qiu
AU - Tianwen Li
AU - Peng Wang
AU - Tatyana Matveeva
AU - Tanner Boyd
AU - Qingyuan Tang
AU - Jun Xue
AU - Lu Su
AU - Hyemyung Seo
AU - Yi Eve Sun
AU - Tian-Lin Cheng
AU - Jeffrey Schweitzer
AU - Bin Song
PY - 2026
DA - 2026/07/01
JO - Stem Cell Research & Therapy
DO - 10.1186/s13287-026-05186-z
UR - https://doi.org/10.1186/s13287-026-05186-z
AB - Background Transplantation of midbrain dopaminergic neurons (mDANs) derived from human pluripotent stem cells (hPSCs) represents a promising therapeutic approach for Parkinson’s disease (PD), with several clinical trials currently in progress. However, the poor survival of grafted mDANs, in part due to inflammation triggered by surgical injury, poses significant challenges to both therapeutic efficacy and safety. In recent years, mesenchymal stem cells (MSCs) and their derivatives have played an important role in the field of stem cell therapy due to their easy accessibility and immunomodulatory properties. However, their potential role as an adjunct in cell therapy remains unclear. Therefore, this study aims to investigate the protective effects of conditioned medium (CM) derived from MSCs and the mechanisms of action by which it attenuates surgery-induced neuroinflammation and enhances the survival of transplanted mDANs. Methods To mimic the neuroinflammatory response caused by the surgical aspect of cell transplantation, transplantation medium alone (i.e. without cells) was injected into the striatum of male NOD SCID mice. The anti-inflammatory effects of MSC-CM in vivo were evaluated by assessing the activation of microglia and expression levels of pro-inflammatory cytokines. Next, an in vitro cell death model was established using IFN-γ and TNF-α stimulation. The protective effects of MSC-CM against IFN-γ and TNF-α-induced inflammatory injury in mDANs were assessed using immunofluorescence staining and TUNEL assay. To identify the active components and underlying mechanisms for the protective effects of MSC-CM, inhibitory treatments, miRNA sequencing, dual-luciferase reporter assay, and subsequent validation by qPCR and Western blotting were performed. Finally, MSC-CM was administered intranasally into male NOD SCID mice following mDAN transplantation to evaluate its protective effects on the grafted mDANs in vivo. Results MSC-CM suppressed neuroinflammation and significantly protected mDANs from inflammation-induced cell death via inhibition of TLR3/NF-κB/p53 signaling pathway in this model system. This protective effect was largely reproduced by treatment with a specific component of the MSC-CM, miR-143-3p. Overexpression of miR-143-3p further enhanced the protective effects and mechanisms of action of MSC-CM. Conclusions This study demonstrates that MSC-CM or its component miR-143-3p exert protective effects on mDANs against inflammatory injury, primarily by inhibiting the TLR3/NFκB/p53 signaling pathway.
SN - 1757-6512
ER -