PPARγ agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes

PLoS One. 2012;7(11):e50500. doi: 10.1371/journal.pone.0050500. Epub 2012 Nov 21.

Abstract

Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14)-Prostaglandin J(2) (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.

MeSH terms

  • Animals
  • Antigens / genetics
  • Antigens / metabolism
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology
  • Gene Expression / drug effects*
  • Glial Fibrillary Acidic Protein
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects*
  • Oligodendroglia / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Proteoglycans / genetics
  • Proteoglycans / metabolism
  • Thiazolidinediones / pharmacology
  • Tretinoin / pharmacology
  • Tubulin / genetics
  • Tubulin / metabolism

Substances

  • 15-deoxyprostaglandin J2
  • Antigens
  • Glial Fibrillary Acidic Protein
  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • PPAR gamma
  • Proteoglycans
  • Thiazolidinediones
  • Tubulin
  • chondroitin sulfate proteoglycan 4
  • glial fibrillary astrocytic protein, mouse
  • Fibroblast Growth Factor 2
  • Tretinoin
  • Epidermal Growth Factor
  • Prostaglandin D2
  • ciglitazone

Grant support

These authors have no support or funding to report.