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Resistin-Inhibited Neural Stem Cell-Derived Astrocyte Differentiation Contributes to Permeability Destruction of the Blood–Brain Barrier

  • Liu Xiaoying
  • Tian Li
  • Shang Yu
  • Jiang Jiusheng
  • Zhang Jilin
  • Wei Jiayi
  • Liu Dongxin
  • Fang Wengang
  • Zhao Xinyue
  • Yu Hao
  • Chen YuhuaEmail author
  • Shang DeshuEmail author
Original Paper
  • 40 Downloads

Abstract

Neuroinflammation is an important part of the development of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s and amyotrophic lateral sclerosis. Inflammatory factors destroy the balance of the microenvironment, which results in changes in neural stem cell differentiation and proliferation behaviour. However, the mechanism underlying inflammatory factor-induced NSC behavioural changes is not clear. Resistin is a proinflammatory and adipogenic factor and is involved in several human pathology processes. The neural stem cell microenvironment changes when the concentration of resistin in the brain during an inflammatory response disease increases. In the present study, we explored the effect and mechanism of resistin on the proliferation and differentiation of neural stem cells. We found that intracerebroventricular injection of resistin induced a decrease in GFAP-positive cells in mice by influencing NSC differentiation. Resistin significantly decreased TEER and increased permeability in an in vitro blood–brain barrier model, which is consistent with the results of an HBMEC-astrocyte coculture system. Resistin-inhibited astrocyte differentiation is mediated through TLR4 on neural stem cells. To our knowledge, this is the first study reporting the effect of resistin on neural stem cells. Our findings shed light on resistin-involved neural stem cell degeneration mechanisms.

Keywords

Resistin Neural stem cell Astrocyte Permeability Blood–brain barrier 

Notes

Acknowledgements

This research was supported by grants from the National Natural Science Foundation of China (Grant Nos. 30600327, 31571057), Liaoning Provincial Department of Education Key Laboratory project (Grant No. LZ2015074), Shenyang Science and Technology Plan Project (Grant Nos. 17-230-9-31 and F16-206-9-03).

Supplementary material

11064_2019_2726_MOESM1_ESM.tif (10 mb)
Supplemental figure 1. Resistin-treated NSCs proliferation in vitro. (A) NSCs were seeded in 96-well plates, resistin at 10 and 100 ng/ml were incubated with NSCs for 12 hours, 24 hours, 36 hours, and 72 hours. Then, 10 μl of CCK8 solution was added to each well and incubated for 4 hours. The OD was measured in a spectrophotometer at 450 nm wavelength. p>0.05 vs. control. (B) Cell cycle of resistin-treated NSCs. NSCs were treated with 10 and 100 ng/ml resistin for 24 hours and 72 hours, and the cell cycle was measured by flow cytometry. (C) Statistical analysis of cell cycle. p>0.05 vs. corresponding controls at different time points. All the experiments were independently performed three times (n=3)—Supplementary material 1 (TIF 10195 KB)
11064_2019_2726_MOESM2_ESM.tif (19.2 mb)
Supplemental figure 2. Effects of resistin on NSC differentiation markers expression under unidirectional culture system. (A) Analysis of immunofluorescence staining. Adherently growing neural stem cells exposed to 10 ng/ml or 100 ng/ml resistin for 7 days in unidirectional differentiation medium. GFAP expression was visualized by immunofluorescence (red) and Nestin expression was visualized by FITC (green). DAPI was used to visualize cell nuclei (blue). Scale bar: 100 μm. (B) Western blot analysis of NSCs differentiation markers GFAP, nestin and PCNA expression. Statistical analysis of nestin (C), GFAP (D) and PCNA (E). One-way ANOVA was used for repeated measurements, n=3, *p<0.05 or **p<0.01 vs. control—Supplementary material 2 (TIF 19634 KB)
11064_2019_2726_MOESM3_ESM.tif (4.3 mb)
Supplemental figure 3. Resistin-induced CD36 Gene and protein expression changes in directed astrocyte differentiation from NSCs. Adherently growing neural stem cells exposed to 10 ng/ml or 100 ng/ml resistin for 7 days in directional differentiation medium. The results of real-time PCR (A) and Western blot (B) show CD36 mRNA and protein levels expression, respectively. One-way ANOVA was used for repeated measurements, n=3, Data are shown as the means ± standard deviations (SD). *p<0.05 or **p<0.01 vs. control—Supplementary material 3 (TIF 4427 KB)
11064_2019_2726_MOESM4_ESM.tif (3 mb)
Supplemental figure 4. Efficiency of transfection. Adherently growing neural stem cells were transfected with 5-carboxy-fluorescein (FAM)-labelled siTLR4 for 24 h. Bright field (A) or fluorescence microscopy (B) shows the efficiency of transfection—Supplementary material 4 (TIF 3115 KB)

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Authors and Affiliations

  1. 1.Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, Ministry of Public HealthChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Deparment of GeriatricsShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China
  3. 3.Class 81, Phase 102China Medical UniversityShenyangPeople’s Republic of China
  4. 4.Department of Developmental Cell Biology, Cell Biology Division, Key Laboratory of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, Ministry of Public HealthChina Medical UniversityShenyangPeople’s Republic of China

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