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Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype

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Abstract

Aims

Epidermal Neural Crest Stem Cells (EPI-NCSCs) have emerged as prospective ideal candidates to meet the fundamental requirements of cell-based therapies in neurodegenerative disorders. The present study aimed to identify the potential of metformin in driving EPI-NCSCs to neuronal/glial differentiation and express neurotrophic factors as well as assess their therapeutic potential for mitigating the main behavioral manifestations of chemotherapy-induced neurotoxicity (CIN).

Main Methods

EPI-NCSCs were extracted from the bulge region of hair follicle. Following expansion, transcript and protein expression profiles of key markers for stemness (Nestin, EGR-1, SOX-2 and 10), neurotrophic activity (BDNF, GDNF, NGF, FGF-2, and IL-6), and neuronal (TUB3, DCX, NRF and NeuN) and glial (PDGFRα, NG2, GFAP, and MBP) differentiation were determined on days 1 and 7 post-treatment with 10 and 100 μM metformin using real time-PCR and immunocytochemistry methods. Then, the in vivo function of metformin-treated stem cells was evaluated in the context of paclitaxel CIN. To do so, thermal hyperalgesia, mechanical allodynia, and spatial learning and memory tests were evaluated by Hotplate, Von Frey, and Morris water maze tests.

Key Findings

Our result indicated that exposure of EPI-NCSCs to metformin was associated with progressive decline in stemness markers and enhanced expression levels of several neurotrophic, neuron and oligodendrocyte-specific markers. Further, it was observed that intranasal metformin-treated EPI-NCSCs improved the cognitive impairment, and mechanical and thermal hypersensitivity induced by paclitaxel in rats.

Significance

Collectively, we reasoned that metformin pretreatment of EPI-NCSCs might further enhance their therapeutic benefits against CIN.

Graphical Abstract

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to express their gratitude to the dedicated staff of the Neuroscience Research Center at Shahid Beheshti University of Medical Sciences for their invaluable technical support. Special appreciation is extended to Dr. Farzin Kamari from the Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany, for his significant contributions, which enhanced both the visual and scientific aspects of this manuscript. The graphical abstract was produced using the tools provided by Biorender.com.

Funding

This study was funded by Research Affairs of Shahid Beheshti University of Medical Sciences, Tehran, Iran (grant No. 26873).

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Authors and Affiliations

  1. Institute of Physiology, Department Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany

    Pariya Khodabakhsh

  2. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Afsaneh Asgari Taei

  3. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Hamed Shafaroodi

  4. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Safura Pournajaf

  5. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi

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  1. Pariya Khodabakhsh
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Contributions

Pariya Khodabakhsh and Afsaneh Asgari Taei: Investigation, Formal analysis, Writing – original draft, Writing – review & editing. Hamed Shafaroodi: Conceptualization, Supervision, Resources. Safura Pournajaf: Investigation, Writing – original draft, Writing – review & editing. Leila Dargahi: Conceptualization, Methodology, Supervision, Resources, Funding acquisition, Writing – review & editing. All authors have approved the manuscript.

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Correspondence to Leila Dargahi.

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All animal experiments were performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23, revised, 1996) and were approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.PHNS.REC.1399.164).

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Khodabakhsh, P., Asgari Taei, A., Shafaroodi, H. et al. Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype. Stem Cell Rev and Rep 20, 394–412 (2024). https://doi.org/10.1007/s12015-023-10642-x

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