Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis

Glia. 2018 Jan;66(1):145-160. doi: 10.1002/glia.23233. Epub 2017 Sep 22.


The generation of new oligodendrocytes is essential for adult brain repair in diseases such as multiple sclerosis. We previously identified the multifunctional p57kip2 protein as a negative regulator of myelinating glial cell differentiation and as an intrinsic switch of glial fate decision in adult neural stem cells (aNSCs). In oligodendroglial precursor cells (OPCs), p57kip2 protein nuclear exclusion was recently found to be rate limiting for differentiation to proceed. Furthermore, stimulation with mesenchymal stem cell (MSC)-derived factors enhanced oligodendrogenesis by yet unknown mechanisms. To elucidate this instructive interaction, we investigated to what degree MSC secreted factors are species dependent, whether hippocampal aNSCs respond equally well to such stimuli, whether apart from oligodendroglial differentiation also tissue integration and axonal wrapping can be promoted and whether the oligodendrogenic effect involved subcellular translocation of p57kip2. We found that CC1 positive oligodendrocytes within the hilus express nuclear p57kip2 protein and that MSC dependent stimulation of cultured hippocampal aNSCs was not accompanied by nuclear p57kip2 exclusion as observed for parenchymal OPCs after spontaneous differentiation. Stimulation with human MSC factors was observed to equally promote rat stem cell oligodendrogenesis, axonal wrapping and tissue integration. As forced nuclear shuttling of p57kip2 led to decreased CNPase- but elevated GFAP expression levels, this indicates heterogenic oligodendroglial mechanisms occurring between OPCs and aNSCs. We also show for the first time that dominant pro-oligodendroglial factors derived from human fetal MSCs can instruct human induced pluripotent stem cell-derived NSCs to differentiate into O4 positive oligodendrocytes.

Keywords: heterogeneity; inhibitors; intracellular protein shuttling; multiple sclerosis; myelin repair; neuroregeneration; oligodendrocyte.

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
  • Animals
  • Animals, Newborn
  • Autophagy-Related Proteins
  • Brain / metabolism
  • Cell Differentiation / drug effects*
  • Cell Nucleolus / drug effects
  • Cell Nucleolus / metabolism
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism
  • Female
  • Fetus
  • Gene Expression Regulation / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / cytology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mesenchymal Stem Cells / cytology
  • Neural Stem Cells / chemistry*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / transplantation
  • Oligodendroglia / drug effects*
  • Oligodendroglia / physiology
  • Rats
  • Rats, Wistar


  • Autophagy-Related Proteins
  • Culture Media, Conditioned
  • Cyclin-Dependent Kinase Inhibitor p57
  • Glial Fibrillary Acidic Protein
  • Intracellular Signaling Peptides and Proteins
  • Rb1cc1 protein, mouse
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases