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Dimethyl fumarate prevents cytotoxicity and apoptosis mediated by oxidative stress in human adipose-derived mesenchymal stem cells

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Abstract

Background

The poor survival rate and undesirable homing of transplanted stem cells are the major challenges in stem cell therapy. Addressing the challenge would improve the therapeutic efficacy of these cells. Dimethyl fumarate (DMF) is an anti-inflammatory drug that exerts its effects through the activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway. Therefore, its cytoprotective effects on human adipose-derived MSCs (hASCs) against various oxidative stresses have been investigated in this study.

Methods and results

hASCs were cultured with different concentrations of DMF to evaluate the cytotoxicity of DMF on hASCs using Cell Counting Kit-8 (CCK-8). Besides, the migration ability of the cells after DMF treatment was evaluated using the Transwell method. Furthermore, the expression of HO-1 and NQO-1 was determined using RT-PCR. The cytoprotective effects of DMF on hASCs against the oxidative stress caused by H2O2 and Ultra Violet (UV) were evaluated by assessing cell proliferation and apoptosis. Our results demonstrated that under oxidative stress conditions induced by H2O2 and UV, DMF increased the survival rate and proliferation of the cells and prevented apoptosis. Moreover, the expression of HO-1 and NQO-1 was upregulated in hASCs pretreated with DMF which confirms the activation of the Nrf2 pathway. However, DMF significantly decreased migration in hADSCs (P < 0.0001).

Conclusion

Our findings indicate that DMF enhances the proliferation capability and viability of hASCs and prevents their apoptosis in harsh stressful microenvironments. However, the applicability of DMF as a cytoprotective factor for the augmentation of hASCs requires in-depth preclinical and clinical studies.

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Data availability

There is no data availability statement provided in the manuscript.

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Acknowledgements

The authors thank Research Deputy of Guilan University of Medical Sciences for their financial support.

Funding

This study has been supported by Guilan University of Medical Sciences (Grant Number: IR.GUMS.REC.1397.410).

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Shima Shekarchi & Mohammad Hadi Bahadori

  2. Burn and Regenerative Medicine Research Center, School of Medicine, Velayat Hospital, Guilan University of Medical Sciences, Rasht, Iran

    Amaneh Mohammadi Roushandeh & Mehryar Habibi Roudkenar

Authors
  1. Shima Shekarchi
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  2. Amaneh Mohammadi Roushandeh
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  3. Mehryar Habibi Roudkenar
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  4. Mohammad Hadi Bahadori
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Contributions

SS: Methodology, statistical analysis, preparation of manuscript draft. AMR: Conceptualization, Methodology, statistical analysis, Editing the manuscript, supervision. MHR: Conceptualization, Editing the manuscript. MHB: Conceptualization, supervision.

Corresponding authors

Correspondence to Amaneh Mohammadi Roushandeh or Mohammad Hadi Bahadori.

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Conflict of interest

There is no conflict interest among authors.

Ethical approval

All processes in this study were approved by ethic committee of Guilan University of Medical Sciences (Ethic approval number: IR.GUMS.REC.1397.410).

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Supplementary Information

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Supplementary file1 (DOCX 13 kb)

Supplementary file2 (DOCX 14 kb)

11033_2021_6638_MOESM3_ESM.jpg

Supplementary file3 (JPG 310 kb) Supplementary Fig. 1 Characterization of adipose-derived mesenchymal stem cells detected by cells morphology, flowcytometry and their multilineage differentiation. (a) Morphology of the cells on day 4 (A), 7 (B), 11 (C) and 15 (D). (Scale bars=200 μm). (b) Flow cytometry for hASCs positive markers CD90, CD105 and CD73 (A, C, E), and hematopoietic markers, CD34 and CD45 (B and D). (F) Differentiation of hASCs to adipocytes (black arrows) and (G) shows the differentiation of the cells into osteocytes (white arrows). (Scale bar = 50µm) (Scale bar = 200 µm)

11033_2021_6638_MOESM4_ESM.jpg

Supplementary file4 (JPG 337 kb) Supplementary Fig. 2 The cytotoxicity of Dimethyl fumarate (DMF) on hASCs in different concentrations and times. (a) Cell morphology after treatment of the cells with different concentrations of DMF for 24 hours (Scale bar = 50µm). (b) Cell viability and proliferation of hASCs were assessed after treatment of the cells with different concentrations of DMF (0, 5,10,20,30,40,50,60,70,80,90, and 100 μM) for 4, 12, 24 and 48 hours. (A-D) *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, ns; non-significant, N; triplicates

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Shekarchi, S., Roushandeh, A.M., Roudkenar, M.H. et al. Dimethyl fumarate prevents cytotoxicity and apoptosis mediated by oxidative stress in human adipose-derived mesenchymal stem cells. Mol Biol Rep 48, 6375–6385 (2021). https://doi.org/10.1007/s11033-021-06638-w

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  • DOI: https://doi.org/10.1007/s11033-021-06638-w

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