The plasticity of primary microglia and their multifaceted effects on endogenous neural stem cells in vitro and in vivo

J Neuroinflammation. 2018 Aug 13;15(1):226. doi: 10.1186/s12974-018-1261-y.


Background: Microglia-the resident immune cells of the brain-are activated after brain lesions, e.g., cerebral ischemia, and polarize towards a classic "M1" pro-inflammatory or an alternative "M2" anti-inflammatory phenotype following characteristic temporo-spatial patterns, contributing either to secondary tissue damage or to regenerative responses. They closely interact with endogenous neural stem cells (NSCs) residing in distinct niches of the adult brain. The current study aimed at elucidating the dynamics of microglia polarization and their differential effects on NSC function.

Results: Primary rat microglia in vitro were polarized towards a M1 phenotype by LPS, or to a M2 phenotype by IL4, while simultaneous exposure to LPS plus IL4 resulted in a hybrid phenotype expressing both M1- and M2-characteristic markers. M2 microglia migrated less but exhibit higher phagocytic activity than M1 microglia. Defined mediators switched microglia from one polarization state to the other, a process more effective when transforming M2 microglia towards M1 than vice versa. Polarized microglia had differential effects on the differentiation potential of NSCs in vitro and in vivo, with M1 microglia promoting astrocytogenesis, while M2 microglia supported neurogenesis. Regardless of their polarization, microglia inhibited NSC proliferation, increased NSC migration, and accelerated NSC differentiation.

Conclusion: Overall, this study shed light on the complex conditions governing microglia polarization and the effects of differentially polarized microglia on critical functions of NSCs in vitro and in vivo. Refining the understanding of microglia activation and their modulatory effects on NSCs is likely to facilitate the development of innovative therapeutic concepts supporting the innate regenerative capacity of the brain.

Keywords: Cerebral ischemia; Hybrid microglia; M1 microglia; M2 microglia; Neuroinflammation; Neuroprotection; Stem cell-mediated regeneration.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation / physiology
  • Cell Movement / drug effects
  • Cell Polarity / drug effects
  • Cell Polarity / genetics
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Interleukin-4 / pharmacology
  • Interleukin-6 / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Microglia / drug effects
  • Microglia / physiology*
  • Microglia / ultrastructure
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Phagocytosis / physiology
  • Rats
  • Rats, Wistar
  • Tumor Necrosis Factor-alpha / metabolism


  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • L-Lactate Dehydrogenase
  • Nitric Oxide Synthase Type II