Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways

Acta Pharmacologica Sinica volume 41, pages612–619(2020)Cite this article

Abstract

Increasing studies show that inflammatory processes may be involved in depressive disorders. Nuclear factor erythroid-2 related factor 2 (Nrf2) modulates tissue microglial M1 phenotypic changes to the M2 phenotype, which is implicated in protection against inflammatory diseases. We have reported that the adipose-derived mesenchymal stem cells (ADSCs) display anti-inflammatory activity. In this study we explored whether the mechanism of anti-inflammatory activity of ADSCs was related to Nrf2. ADSCs were isolated from mouse fat pads and intravenously administered to chronic mild stress (CMS)-exposed C57BL/6 mice at the dose of 1 × 106 once a week for 3 weeks. We showed that ADSC administration significantly remedied CMS-induced depressive-like behaviors in sucrose preference test, tail suspension test, and forced swim test accompanied by suppressing microglial activation and the expression of inflammatory factors including MCP-1, TNF-α, IL-1β, and IL-6. Furthermore, ADSC administration promoted both the expression of BDNF and TrkB, and promoted Nrf2/HO-1 signaling but suppressed TLR4/NF-κB signaling in brain tissue. In order to elucidate the role of Nrf2/HO-1 signaling in ADSC-caused neuroprotection, Nrf2-modified ADSCs were cocultured with BV2 microglial cells, then exposed to lipopolysaccharide (LPS). Downregulation of Nrf2 in ADSCs decreased the protective effects of ADSCs against LPS-induced microglial activation and M1 polarization. Nrf2 overexpression in ADSCs markedly suppressed LPS-induced TLR4 and NF-κB expression in microglial cells. These results suggest a possible antidepressive mechanism correlated with microglial polarization for anti-inflammatory agents, which may provide a new microglia-targeted strategy for depression therapy.

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Fig. 1: Characterization of adipose-derived mesenchymal stem cells (ADSCs).
Fig. 2: ADSC treatment reversed chronic mild stress (CMS)-induced depressive-like behaviors.
Fig. 3: ADSC treatment reversed CMS-induced inflammatory factor expression and hippocampal microglial activation.
Fig. 4: Nrf2 and TLR4 played roles in the ADSC-mediated protective effect on neurons.
Fig. 5: The expression of Nrf2 and HO-1 in ADSCs after transfection with an Nrf2 overexpression vector or siRNA targeting Nrf2 (siNrf2).
Fig. 6: ADSC and BV2 cell cocultures showed that Nrf2 plays a role in ADSC-mediated protective effects against LPS-induced inflammatory factor expression in BV2 microglial cells.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31771184).

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Affiliations

  1. Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xiao Huang, Wen-juan Liu, Yuan Wang & Jian-lin Ji

  2. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xiao Huang, Guo-qiang Fei, Jing Ding & Xin Wang

  3. Teaching Center of Experimental Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Hao Wang

  4. The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China

    Xin Wang

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  1. Xiao Huang
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  2. Guo-qiang Fei
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  3. Wen-juan Liu
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  4. Jing Ding
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  5. Yuan Wang
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  6. Hao Wang
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  8. Xin Wang
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Contributions

HW, XW, and JLJ designed the study and wrote the protocols; XH, YW, and GQF managed the literature retrieval and performed the experimental work and data analysis; WJL, JD, and XW wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Hao Wang or Jian-lin Ji or Xin Wang.

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Huang, X., Fei, Gq., Liu, Wj. et al. Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways. Acta Pharmacol Sin 41, 612–619 (2020). https://doi.org/10.1038/s41401-019-0317-6

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Keywords

  • ADSCs
  • Nrf2
  • TLR4
  • microglial
  • chronic mild stress

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