Research ReportEffects of human marrow stromal cells on activation of microglial cells and production of inflammatory factors induced by lipopolysaccharide
Introduction
Microglial cells are the resident immune cells of the central nervous system (CNS). As the source of inflammation, activated microglia produce a variety of inflammatory factors, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and reactive oxygen species. Inflammation in the CNS has been closely associated with the pathogenesis of neural damage resulting from cerebral ischemia and neurodegenerative diseases (Skaper, 2007, Wang et al., 2007). Therefore, the effective control of microglial activation in these neurological diseases is regarded as an important therapeutic target.
Stem cell transplantation is a promising therapeutic strategy for neural damage. Human marrow stromal cells (hMSCs) are isolated from adult bone marrow, and easy access suggests the feasibility in clinical therapies. These cells have the potential to differentiate to lineages of mesenchymal tissues — bone, cartilage, fat, and muscle. Autologous transplantation of hMSCs would circumvent potential ethical and immunological concerns. These advantages suggest that hMSCs may be the suitable candidates for human therapies. A number of studies in animal models suggest that infusion of marrow stromal cells (MSCs) can dramatically lessen neural damage (Chen et al., 2001, Honma et al., 2006, Park et al., 2008, Wu et al., 2007). Even with the encouraging results of cell transplantation, the mechanisms involved have not been defined. The functional replacement of lost motoneurons is proved very difficultly, and more likely cells exert their neuroprotective effects (Phinney and Prockop, 2007). Recently, the anti-inflammatory and immunomodulatory effects of MSCs have generated a great deal of interest (Iyer and Rojas, 2008, Uccelli et al., 2008). Thus, it would not be unexpected that the neuroprotective effects may involve with the anti-inflammatory activity of MSCs.
Here, we investigated if hMSCs attenuate microglial activation and attendant inflammatory factor secretion stimulated by bacterial endotoxin lipopolysaccharide (LPS). In addition, we also focused on the mode of influence on microglial inflammation by hMSCs.
Section snippets
hMSCs inhibited the activation of microglial cells induced by LPS
After stimulation with LPS for 6 h, activated microglia showed an enlarged shape and an intense immunoreactivity for F4/80 antigen, marker for murine microglia, whereas unstimulated microglia showed a small and rounded shape (Figs. 1A–E). The counts of enlarged microglia cultured in hMSCs conditioned medium were similar to that in vehicle-treated cultures (36.5 ± 1.3 versus 35.5 ± 2.1 per field; p > 0.05). Compared with vehicle-treated cultures, hMSCs significantly reduced the number of enlarged
Discussions
In the present study we reported that hMSCs inhibited LPS-stimulated microglial activation and the production of inflammatory factors. Furthermore, our results showed that hMSCs interacted with microglial cells through diffusible molecules. Finally, hMSCs within inflammatory environment could significantly increase the production of neurotrophic factors.
Preparation of hMSCs
After obtained informed consent, 2 ml bone marrow was aspirated from the iliac crest of healthy normal volunteers. The protocol was approved by the Institutional Review Board of Qingdao University. Mononuclear cells (MNCs) were isolated by Ficoll density gradient centrifugation (1.077 g/ml, Sigma, Germany) at 400 ×g for 35 min. MNCs were re-suspended in the culture medium composed of Dulbecco's modified Eagle's medium (DMEM) with low glucose and 10% fetal bovine serum (FBS). MNCs were plated at
Acknowledgment
The work was supported by a grant from Natural Science Fund of Shandong Province (32693).
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