Dear editor,
We found Salehi et al.’s letter [1] very interesting. They proposed to investigate the potential therapeutic effects of epidermal neural crest stem cells (EPI-NCSCs) in covid-19 disease. There are ongoing trials investigating the efficacy of mesenchymal stem cells (MSCs) in treatment of COVID-19. Salehi et al. believed that EPI-NCSCs might be superior to MSCs due to their high proliferation ability, multi-lineage potential, and lower risk of carcinogenicity. EPI-NCSCs are potent sources of growth factors including fibroblast growth factor (FGF), Transforming growth factor (TGF), Insulin-like growth factor 1 (IGF),Vascular endothelial growth factor (VEGF), Brain derived neurotrophic factors (BDNF), Neurotrophin-3 (NT-3), Nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). The results of a very recent clinical trial which investigated the therapeutic effects of mesenchymal stem cells (MSCs) in covid-19 patients showed the overexpression of major growth factors in transplanted MSCs [2].
Salehi et al. very briefly described, the beneficial effects of the combination of stem cells and pharmacologic agents in various diseases. This writing is a complementary letter on the potential therapeutic benefits of Dimethyl fumarate (DMF) and EPI-NCSCs combination therapy in covid-19 infection.
Dimethyl fumarate (DMF) and its dynamic metabolite mono methyl fumarate (MMF) have been firstly introduced as a treatment of psoriasis. Its clinical application was then extended to cure relapsing remitting Multiple Sclerosis (RRMS). Its anti-inflammatory and anti-oxidants effects, particularly through activating nuclear factor erythroid-derived 2(E2)‐related factor (Nrf-2) have been reported [3]. Suppressing nuclear translocation of nuclear factor‐κB (NF-κB) and enhancing the expression of hydroxyl carboxylic acid receptor (HCAR) were also introduced as the other main mechanisms of action. Regulation of NF-κB activity was reported to be effective in treating Covid-19 infection [4]. The vast anti-inflammatory effects of HCAR in various organs were also reported [5].
DMF, was recently proposed as a potential therapeutic option for Covid-19 patients. Its potential benefits in reducing alveolar cell injury were explained thoroughly with a focus on its Nrf-2 activating mechanisms of action [6]. Virus entry and replication were also explained to be negatively affected by DMF. Activating secretory leukocyte protease inhibitor (SLPI) as an anti-protease and inhibiting transmembrane protease serine 2 (TMRPSS2) as a protease protein were the main mechanisms introduced. Enhancing the expression of anti-viral genes retinoic acid-inducible gene-I (RIG-I) and Interferon beta (IFN-β) were presented as the other potential benefits of DMF therapy in covid-19 patients [6]. DMF and MMF also exert a huge immunomodulatory effects through regulating a wide range of immune cells that determine the host innate and acquired immune response. DMF can effectively change the T- helper cells profile from type 1 to type 2. Not only B and T cells but also macrophages, dendritic and natural killer cells are affected [6]. The final result of these vast regulatory effects can be the inhibition of cytokine storm which is known as the main triggered factor for the disease severity in covid-19 patients. The results of a new case series recommended the continuation of DMF therapy in younger MS patients with normal lymphocyte count who become infected with COVID-19 in their course of therapy [7]. Other researchers also confirmed the safety of starting DMF treatment in healthy young or pediatric MS patients [7].
Combination of stem cell therapy with pharmacologic agents have been vastly investigated in a wide range of disease models. Our recent investigation demonstrated that DMF effectively induced the over expression of EPI-NCSCs trophic factors profile, particularly those with neurotrophic effects [8]. The enhanced trophic factor profile of MSCs applied in treatment of covid-19 patients [2] can be assumed as a potential therapeutic effect of stem cells in this infection.
According to above-mentioned findings, it can be assumed that DMF-treated EPI-NCSCs may have even more beneficial effects in treatment of SARS-Cov-2 infection than EPI-NCSCs. Considering the previous reports on the beneficial effects of both EPI-NCSCs [9] and DMF [10] in neurological disorders, DMF- treated EPI-NCSCs may possess the greater advantages in neurological complications of SARS-Cov-2 infection.
Footnotes
This article belongs to the Topical Collection: Special Issue on COVID-19 Pandemic and Stem Cells
Guest Editor: Mariusz Z. Ratajczak
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References
- 1.Salehi, M. S., Pandamooz, S., & Jurek, B. (2020). Epidermal neural crest stem cells as a perspective for COVID-19 treatment. Stem Cell Reviews and Reports, 1–2. 10.1007/s12015-020-10028-3. [DOI] [PMC free article] [PubMed]
- 2.Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Zhao RC. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging and Disease. 2020;11(2):216–228. doi: 10.14336/AD.2020.0228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Safari A, Badeli-Sarkala H, Namavar MR, Kargar-Abarghouei E, Anssari N, Izadi S, Borhani-Haghighi A. Neuroprotective effect of dimethyl fumarate in stroke: The role of nuclear factor erythroid 2-related factor 2. Iranian Journal of Neurology. 2019;18(3):108–113. [PMC free article] [PubMed] [Google Scholar]
- 4.Elkhodary M. Treatment of COVID-19 by controlling the activity of the nuclear factor-Kappa B. CellBio. 2020;09:109–121. doi: 10.4236/cellbio.2020.92006. [DOI] [Google Scholar]
- 5.Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism: Clinical and Experimental. 2016;65(2):102–113. doi: 10.1016/j.metabol.2015.10.001. [DOI] [PubMed] [Google Scholar]
- 6.Hassan SM, Jawad MJ, Ahjel SW, Singh RB, Singh J, Awad SM, Hadi NR. The Nrf2 activator (DMF) and Covid-19: Is there a possible role? Medical Archives (Sarajevo, Bosnia and Herzegovina) 2020;74(2):134–138. doi: 10.5455/medarh.2020.74.134-138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mantero, V., Abate, L., Basilico, P., Balgera, R., Salmaggi, A., Nourbakhsh, B., & Cordano, C. (2020). COVID-19 in dimethyl fumarate-treated patients with multiple sclerosis. Journal of Neurology. 10.1007/s00415-020-10015-1. [DOI] [PMC free article] [PubMed]
- 8.Salehi MS, Borhani-Haghighi A, Pandamooz S, Safari A, Dargahi L, Dianatpour M, Tanideh N. Dimethyl fumarate up-regulates expression of major neurotrophic factors in the epidermal neural crest stem cells. Tissue and Cell. 2019;56:114–120. doi: 10.1016/j.tice.2019.01.004. [DOI] [PubMed] [Google Scholar]
- 9.Salehi MS, Pandamooz S, Safari A, Jurek B, Tamadon A, Namavar MR, Borhani-Haghighi A. Epidermal neural crest stem cell transplantation as a promising therapeutic strategy for ischemic stroke. CNS Neuroscience & Therapeutics. 2020;26(7):670–681. doi: 10.1111/cns.13370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Safari A, Fazeli M, Namavar MR, Tanideh N, Jafari P, Borhani-Haghighi A. Therapeutic effects of oral dimethyl fumarate on stroke induced by middle cerebral artery occlusion: An animal experimental study. Restorative Neurology and Neuroscience. 2017;35(3):265–274. doi: 10.3233/RNN-160670. [DOI] [PubMed] [Google Scholar]