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

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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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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The authors declare no competing interests.

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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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