Human Mesenchymal Stem Cell Subpopulations Express a Variety of Neuro-Regulatory Molecules and Promote Neuronal Cell Survival and Neuritogenesis

Exp Neurol. 2006 Mar;198(1):54-64. doi: 10.1016/j.expneurol.2005.10.029. Epub 2005 Dec 5.

Abstract

Mesenchymal stem cells (MSCs) transplanted at sites of nerve injury are thought to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. To evaluate this phenomenon further, we quantified in human MSCs neurotrophin expression levels and their effects on neuronal cell survival and neuritogenesis. Screening a human MSC cDNA library revealed expressed transcripts encoding BDNF and beta-NGF but not NT-3 and NT-4. Immunostaining demonstrated that BDNF and beta-NGF proteins were restricted to specific MSC subpopulations, which was confirmed by ELISA analysis of 56 separate subclones. Using a co-culture assay, we also demonstrated that BDNF expression levels correlated with the ability of MSC populations or subclones to induce survival and neurite outgrowth in the SH-SY5Y neuroblastoma cell line. However, these MSC-induced effects were only partially inhibited by a neutralizing anti-BDNF antibody. MSCs were also shown to promote neurite outgrowth within dorsal root ganglion explants despite secreting 25-fold lower level of beta-NGF required exogenously to produce a similar effect. Interrogation of the human MSC transcriptome identified expressed mRNAs encoding various neurite-inducing factors, axon guidance and neural cell adhesion molecules. Moreover, a subset of these transcripts was shown to correlate with BDNF expression in MSC subclones. Collectively, these studies reveal the existence of MSC subpopulations that co-express neurotrophins and other potent neuro-regulatory molecules, which contribute to MSC-induced effects on neuronal cell survival and nerve regeneration. These subpopulations may represent more potent vectors for treating a variety of neurological disorders.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Brain-Derived Neurotrophic Factor / immunology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cell Count / methods
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Coculture Techniques / methods
  • Enzyme-Linked Immunosorbent Assay / methods
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Humans
  • Mesenchymal Stem Cells / classification
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Nerve Growth Factors / metabolism*
  • Neurites / drug effects
  • Neurites / physiology*
  • Neurons / cytology*
  • Neurons / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Time Factors
  • Tretinoin / pharmacology

Substances

  • Brain-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Tretinoin