Menstrual blood-derived endometrial stem cells inhibit neuroinflammation by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 pathway

Zhihao Xu; Guoqing Zhang; Xiaoyue Zhang; Yu Lei; Yuliang Sun; Ya'nan He; Fen Yang; Wenbin Nan; Xuekun Xing; Yonghai Li; Juntang Lin

doi:10.1016/j.biocel.2023.106386

Menstrual blood-derived endometrial stem cells inhibit neuroinflammation by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 pathway

Int J Biochem Cell Biol. 2023 Apr:157:106386. doi: 10.1016/j.biocel.2023.106386. Epub 2023 Feb 6.

Authors

Zhihao Xu¹, Guoqing Zhang², Xiaoyue Zhang², Yu Lei³, Yuliang Sun⁴, Ya'nan He⁵, Fen Yang⁴, Wenbin Nan³, Xuekun Xing⁶, Yonghai Li², Juntang Lin⁷

Affiliations

¹ School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China. Electronic address: zhihao220@xxmu.edu.cn.
² School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China.
³ School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China.
⁴ Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China; School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan, PR China.
⁵ Zhongyuan Stem Cell Research Institute, Xinxiang 453003, Henan, PR China.
⁶ College of Public Health, Guilin Medical University, Guilin 541199, Guangxi, PR China.
⁷ School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China; School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan, PR China. Electronic address: linjt@xxmu.edu.cn.

PMID: 36754162
DOI: 10.1016/j.biocel.2023.106386

Abstract

Neuroinflammation is a common response in various neurological disorders. Mesenchymal stem cell-based treatment has become a promising therapy for neuroinflammation-associated diseases. However, the effects of mesenchymal stem cells are controversial, and the underlying mechanism is incompletely understood. In the present study, menstrual blood-derived endometrial stem cells were intravenously transplanted into a mouse model of neuroinflammation established by peripheral injection of lipopolysaccharide. Microglial cells challenged with lipopolysaccharide were cultured with conditioned medium from endometrial stem cells. The levels of cytokines were detected by enzyme-linked immunosorbent assay. Cell proliferation and death were detected by Cell Counting Kit 8 and flow cytometry, respectively. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (Casp1) were evaluated by western blotting. The results showed that intravenous transplantation of endometrial stem cells downregulated proinflammatory factors and upregulated anti-inflammatory factors in the brain of mice with neuroinflammation. Conditioned medium suppressed the inflammatory reaction and hyperactivation of microglial cells and protected microglial cells from cell death induced by lipopolysaccharide in vitro. The expression of TLR4, MyD88, NLRP3 and Casp1 in the brain of mice with neuroinflammation and in lipopolysaccharide-stimulated microglial cells was downregulated by endometrial stem cells and conditioned medium, respectively. These data suggested that menstrual blood-derived endometrial stem cells may suppress neuroinflammatory reactions partially by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 signalling pathway. Our findings may be very useful for the development of an alternative stem cell-based therapy for neuroinflammation-associated disorders.

Keywords: Mesenchymal stem cells; Microglia; NLRP3; Neuroinflammation; TLR4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caspase 1 / metabolism
Culture Media, Conditioned / metabolism
Culture Media, Conditioned / pharmacology
Lipopolysaccharides / toxicity
Mice
Microglia* / metabolism
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Neuroinflammatory Diseases
Toll-Like Receptor 4 / genetics

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Myeloid Differentiation Factor 88
Toll-Like Receptor 4
Caspase 1
Lipopolysaccharides
Culture Media, Conditioned
NF-kappa B
Myd88 protein, mouse
Nlrp3 protein, mouse
Tlr4 protein, mouse