ieAstrocytes: Newly Identified Functionally Active Astrocyte Population in a Mouse Model of Multiple Sclerosis
This article was a highlight for me because Groves and colleagues identified an in vivo population of astrocytes that are functionally active and increase in number as the severity of experimental autoimmune encephalomyelitis (EAE) progresses. EAE can be induced by immunization with MOG35-55 peptide and serves as an animal model of multiple sclerosis. Four-dimensional (3D over time) imaging was used to visualize the time course of cells in the spinal cord that became activated in response to EAE. The use of inducible, TetTag c-Fos reporter mice enabled stable, nuclear expression of green fluorescent protein (GFP) to be retained in cells upon activation. This represented an unbiased screen as the immediate-early gene c-fos is a marker of cellular activation in all cell types. Combined tissue clearing (iDISCO) and confocal microscopy showed that from day 1-5 post onset (dpo 1–5) of EAE, the number of GFP-positive (GFP+) cells in the spinal cord increased in a manner that positively correlated with the severity of EAE symptoms (Video 1; 5 dpo). Approximately 95% of the GFP+ cells at 5 dpo were identified as astrocytes. Groves and colleagues coined the term “immediately-early astrocytes” (ieAstrocytes) for this functionally active population of astrocytes that are distinct from quiescent astrocytes. FTY720 (fingolimod), an effective, well-tolerated treatment for relapsing forms of multiple sclerosis, can be phosphorylated in vivo to resemble the endogenous ligand for the sphingosine 1-phosphate receptor 1 (S1P1). When Groves and colleagues induced EAE in mice in which S1P1 was specifically deleted in astrocytes, the number of GFP+ cells at 5 dpo was significantly attenuated (Video 2). Similar attenuation of GFP immunoreactivity was observed at 5 dpo in EAE-induced S1P1 wild-type mice that were treated with FTY720 (Video 3). This study is an important advance in the field because it shows an in vivo temporal and spatial response of ieAstrocytes to EAE disease progression, which is modified by a drug currently used in the treatment of multiple sclerosis. Further targeting of ieAstrocytes by other therapeutic mechanisms could be highly relevant to other neurodegenerative and neuroinflammatory brain disorders.
Video 1. GFP+ cells at 5 dpo of EAE (Video 5 in Groves et al., 2018)
Video 2. GFP+ cells at 5 dpo of EAE in a conditional knockout of S1P1 in astrocytes (Video 6 in Groves et al., 2018)
Video 3. GFP+ cells at 5 dpo S1P1 wild-type mice treated with FTY720 (Video 7 in Groves et al., 2018)
Read the full article:A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes)
Aran Groves, Yasuyuki Kihara, Deepa Jonnalagadda, Richard Rivera, Grace Kennedy, Mark Mayford, and Jerold Chun