title: Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase.
abstract: 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.
authors.affiliation: Department of Biology, College of Natural Science, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Korea.|Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, 501-759, Korea.
authors.forename: Youn Seo
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.|Cell Therapy Center, Hanyang University Hospital, Seoul, Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biology, College of Natural Science, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Korea. gwcho@chosun.ac.kr.|Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, 501-759, Korea. gwcho@chosun.ac.kr.
authors.forename: Goang-Won
authors.initials: GW
authors.lastname: Cho
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects; D010797:Phthalimides / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010797:Phthalimides; C503639:RG108; D014364:Tryptophan; D015254:DNA Modification Methylases
keywords: Amyotrophic lateral sclerosis (ALS); Bone marrow mesenchymal stromal cells (BM-MSCs); DNA methyltransferases (DNMTs); DNMT inhibition; RG108