Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase
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Alteration of DNA methylation is highly associated with aging and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Remedying these aberrant methylation patterns may serve to improve these diseases. Previously, we reported that human bone marrow mesenchymal stromal cells isolated from ALS patients (ALS-MSCs) have functionally decreased stem cell potency, and excessively express DNA methyltransferases (DNMTs). In this study, we examined the correlation between excessive DNMT expression and functional decline in ALS-MSCs. The DNMT inhibitor RG108 was used for this. RG108-treated ALS-MSCs exhibit increased expression of the anti-senescence genes TERT, VEGF, and ANG, and decreased expression of the senescence-related genes ATM and p21. The activity of SA-β-galactosidase and the expression of senescence proteins p53 and p16 were reduced in RG108-treated ALS-MSCs. The abilities of cell migration and protection against oxidative damage were improved in the treated ALS-MSCs. In neuronal differentiation experiments, the treated MSCs more effectively differentiated into neuron-like cells. These results suggest that ALS-MSC function can be restored by inhibiting excessively expressed DNMTs, an approach that may ultimately provide better efficacy in stem cell therapy.
KeywordsBone marrow mesenchymal stromal cells (BM-MSCs) Amyotrophic lateral sclerosis (ALS) DNA methyltransferases (DNMTs) DNMT inhibition RG108
Amyotrophic lateral sclerosis
Ataxia telangiectasia mutated
Bone marrow mesenchymal stromal cells
Fetal bovine serum
Mesenchymal stromal cells
Polymerase chain reaction
- SA-β-gal staining
Senescence-associated beta-galactosidase staining
Vascular endothelial growth factor
This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A120203), a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2010-0010431).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
The manuscript does not contain clinical studies or patient data.
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