Luteolin Modulates Neural Stem Cells Fate Determination: In vitro Study on Human Neural Stem Cells, and in vivo Study on LPS-Induced Depression Mice Model.

Mariem Achour,Hiroko Isoda,Farhana Ferdousi,Kazunori Sasaki

doi:10.3389/fcell.2021.753279

Abstract

Luteolin is a natural flavone with neurotrophic effects observed on different neuronal cell lines. In the present study, we aimed to assess the effect of luteolin on hNSCs fate determination and the LPS-induced neuroinflammation in a mouse model of depression with astrocytogenesis defect. hNSCs were cultured in basal cell culture medium (control) or medium supplemented with luteolin or AICAR, a known inducer of astrogenesis. A whole-genome transcriptomic analysis showed that luteolin upregulated the expressions of genes related to neurotrophin, dopaminergic, hippo, and Wnt signaling pathways, and downregulated the genes involved in p53, TNF, FOXO, and Notch signaling pathways. We also found that astrocyte-specific gene GFAP, as well as other genes of the key signaling pathways involved in astrogenesis such as Wnt, BMP, and JAK-STAT pathways were upregulated in luteolin-treated hNSCs. On the other hand, neurogenesis and oligodendrogenesis-related genes, TUBB3, NEUROD 1 and 6, and MBP, were downregulated in luteolin-treated hNSCs. Furthermore, immunostaining showed that percentages of GFAP+ cells were significantly higher in luteolin- and AICAR-treated hNSCs compared to control hNSCs. Additionally, RT-qPCR results showed that luteolin upregulated the expressions of GFAP, BMP2, and STAT3, whereas the expression of TUBB3 remained unchanged. Next, we evaluated the effects of luteolin in LPS-induced mice model of depression that represents defects in astrocytogenesis. We found that oral administration of luteolin (10 mg/Kg) for eight consecutive days could decrease the immobility time on tail suspension test, a mouse behavioral test measuring depression-like behavior, and attenuate LPS-induced inflammatory responses by significantly decreasing IL-6 production in mice brain-derived astrocytes and serum, and TNFα and corticosterone levels in serum. Luteolin treatment also significantly increased mature BDNF, dopamine, and noradrenaline levels in the hypothalamus of LPS-induced depression mice. Though the behavioral effects of luteolin did not reach statistical significance, global gene expression analyses of mice hippocampus and brain-derived NSCs highlighted the modulatory effects of luteolin on different signaling pathways involved in the pathophysiology of depression. Altogether, our findings suggest an astrocytogenic potential of luteolin and its possible therapeutic benefits in neuroinflammatory and neurodegenerative diseases. However, further studies are required to identify the specific mechanism of action of luteolin.

Highlights

Neural stem cells (NSCs) are self-renewal cells that can be differentiated into neurons or glial cells following neurogenesis and gliogenesis processes, respectively (Apple et al, 2017)
We found that treatment with 1 μM luteolin could significantly regulate the expressions of 5870 genes in hNSCs (−1.3 < Fold change < 1.3; p < 0.05), with upregulation of 2638 genes and downregulation of 3232 genes
The present study is the first to report the effects of the natural flavonoid luteolin on hNSCs fate determination highlighting; its potential beneficial use, especially as an astrogliogenesis promoting compound

Summary

Introduction

Neural stem cells (NSCs) are self-renewal cells that can be differentiated into neurons or glial cells following neurogenesis and gliogenesis processes, respectively (Apple et al, 2017). Defects in astrogenesis or early functions of astrocytes are reported to be involved in the development of different psychiatric disorders (Gonzales et al, 2017; Cohen and Torres, 2019; Pajarillo et al, 2019; Valles et al, 2019) Both neurons and astrocytes should be targeted simultaneously to re-establish the physiological functions in damaged brain. The increasing incidences of lack of efficacy and undesirable side effects of existing pharmacological intervention have led to particular attention to several medicinal plants and their bioactive compounds In this context, different studies have reported the ability of phytochemicals to target NSCs for inducing brain self-repair through modulating neurogenesis (Matias et al, 2016; Gonzales et al, 2017; Sasaki et al, 2019)

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