Cellular and Molecular Neurobiology

, Volume 36, Issue 4, pp 613–620 | Cite as

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Original Research

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.

Keywords

Bone marrow mesenchymal stromal cells (BM-MSCs) Amyotrophic lateral sclerosis (ALS) DNA methyltransferases (DNMTs) DNMT inhibition RG108 

Abbreviations

ALS

Amyotrophic lateral sclerosis

ANG

Angiogenin

ATM

Ataxia telangiectasia mutated

BHA

Butyalated hydroxyanisole

BM-MSCs

Bone marrow mesenchymal stromal cells

DMSO

Dimethyl sulfoxide

DNMTs

DNA methyltransferases

FBS

Fetal bovine serum

MMPs

Metalloproteinase

MSCs

Mesenchymal stromal cells

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PBS

Phosphate-buffered saline

PCR

Polymerase chain reaction

RIPA

Radioimmunoprecipitation assay

SA-β-gal staining

Senescence-associated beta-galactosidase staining

TERT

Telomerase

VEGF

Vascular endothelial growth factor

Supplementary material

10571_2015_242_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Youn Seo Oh
    • 1
    • 2
  • Seung Hyun Kim
    • 3
    • 4
  • Goang-Won Cho
    • 1
    • 2
  1. 1.Department of Biology, College of Natural ScienceChosun UniversityGwangjuKorea
  2. 2.Department of Life Science, BK21-Plus Research Team for Bioactive Control TechnologyChosun UniversityGwangjuKorea
  3. 3.Department of NeurologyHanyang University College of MedicineSeoulKorea
  4. 4.Cell Therapy CenterHanyang University HospitalSeoulKorea

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