Astrocytes Regulate Differentiation and Glutamate Uptake of Glioma Stem Cells via Formyl Peptide Receptor
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ORIGINAL RESEARCH
Astrocytes Regulate Differentiation and Glutamate Uptake of Glioma Stem Cells via Formyl Peptide Receptor Ya‑Wen Xu1 · Jin‑Shan Yang2 · De‑Zhi Kang1 · Pei‑Sen Yao1 Received: 20 March 2020 / Accepted: 25 May 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The role of astrocytes on glutamate release and differentiation of glioma stem cells (GSCs) remains unknown. We investigated glutamate release, proliferation, and differentiation of GSCs after indirect incubation with astrocytes in vitro, including morphology change, GFAP expression, glutamine synthetase, and EAAT1 expression. The role of formyl peptide receptor (FPR) agonist and antagonist on interaction between astrocytes and GSCs in co-culture model was analyzed. We found: (1) After incubation of astrocytes and GSCs, differentiated GSCs present the morphology of astrocytes and express GFAP. (2) GSCs release high concentration of glutamate, as well as tumor cells. However, differentiated GSCs possess the ability of glutamate uptake. (3) Proliferation ability of differentiated GSCs is lower than tumor cells. (4) Glutamine synthetase is predominantly expressed in the nucleus of tumor cells, while in the cytoplasm of differentiated GSCs. (5) Differentiation of GSCs could be triggered by FPR agonist, while astrocyte-induced differentiation of GSCs could be blocked by FPR antagonist. These results indicate astrocytes promote astrocytic differentiation and glutamate uptake of GSCs via FPR. Keywords Glutamate · Glutamine · Astrocytes · Glioma
Introduction Glioblastoma (GBM) has shown to release a high amount of glutamate (Ye and Sontheimer 1999), which contributes to the growth of gliomas and neuronal injury (Erecinska and Silver 1990; Takano et al. 2001; Piao et al. 2009). Previous studies indicated that inhibition of glioma glutamate release inhibited the growth of glioma (Lyons et al. 2007; Ishiuchi et al. 2002). Physiologically, glutamate is released from neurons and absorbed by astrocytes (Bak et al. 2006; Martinez-Hernandez et al. 1977; Hertz 1979; Hertz et al. 1999). Pathologically, extracellular glutamate released by Ya-Wen Xu and Jin-Shan Yang equally contributed to this article. * De‑Zhi Kang [email protected] * Pei‑Sen Yao [email protected] 1
Department of Neurosurgery, First Affiliated Hospital of Fujian Medical University, NO. 20 Chazhong Road, Taijiang District, Fuzhou 350004, Fujian, China
Department of Neurology, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
2
glioma cells could be regulated at low levels by surrounding abundant astrocytes (Yao et al. 2014). GSCs are capable of self-renewal, proliferation, differentiation, and multidrug resistance (Jhaveri et al. 2016). Furthermore, GSCs contribute to invasion, recurrence and metastasis of brain glioma (Schonberg et al. 2014; Chen et al. 2012). GSCs could be induced to differentiate into oligodendrocyte-like cells by drugs or cytokines, which induce apoptosis of GSCs and inhibit the growth of GSCs (Yang et
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