Bone marrow-derived mesenchymal stem cells maintain the resting phenotype of microglia and inhibit microglial activation

PLoS One. 2013 Dec 31;8(12):e84116. doi: 10.1371/journal.pone.0084116. eCollection 2013.

Abstract

Many studies have shown that microglia in the activated state may be neurotoxic. It has been proven that uncontrolled or over-activated microglia play an important role in many neurodegenerative disorders. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown in many animal models to have a therapeutic effect on neural damage. Such a therapeutic effect is attributed to the fact that BMSCs have the ability to differentiate into neurons and to produce trophic factors, but there is little information available in the literature concerning whether BMSCs play a therapeutic role by affecting microglial activity. In this study, we triggered an inflammatory response situation in vitro by stimulating microglia with the bacterial endotoxin lipopolysaccharide (LPS), and then culturing these microglia with BMSC-conditioned medium (BMSC-CM). We found that BMSC-CM significantly inhibited proliferation and secretion of pro-inflammatory factors by activated microglia. Furthermore, we found that the phagocytic capacity of microglia was also inhibited by BMSC-CM. Finally, we investigated whether the induction of apoptosis and the production of nitric oxide (NO) were involved in the inhibition of microglial activation. We found that BMSC-CM significantly induced apoptosis of microglia, while no apoptosis was apparent in the LPS-stimulated microglia. Our study also provides evidence that NO participates in the inhibitory effect of BMSCs. Our experimental results provide evidence that BMSCs have the ability to maintain the resting phenotype of microglia or to control microglial activation through their production of several factors, indicating that BMSCs could be a promising therapeutic tool for treatment of diseases associated with microglial activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow / growth & development*
  • Bone Marrow / metabolism
  • Cell Proliferation*
  • Cells, Cultured
  • Chemokines / metabolism
  • Culture Media, Conditioned / pharmacology
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Lipopolysaccharides / pharmacology
  • Male
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism
  • Microglia / cytology*
  • Microglia / metabolism
  • Nitric Oxide / metabolism*
  • Phagocytosis / physiology
  • Phenotype
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Chemokines
  • Culture Media, Conditioned
  • Cytokines
  • Lipopolysaccharides
  • Nitric Oxide

Grant support

This work was supported by grants from the funds for National Key Clinic Department, the Natural Science Fund of China (No. 81171179 and No. 81272439), the Guandong Natural Science Foundation (No. S2013020012754), the Funds for Key Sci-Tech Research Projects of Guangdong (No. 2008A030201019), and Funds for Key Sci-Tech Research Projects of Guangzhou (No. 09B52120112-2009J1-C418-2, No. 2008A1-E4011-6) to professor Xiaodan Jiang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.