Lactate Promotes Reactive Astrogliosis and Confers Axon Guidance Potential to Astrocytes under Oxygen-Glucose Deprivation

Abstract

During cerebral ischemia, brain lactate concentration increases, and astrogliosis is triggered. Herein, we investigated lactate's role in astrogliosis and explored the functions of lactate-activated astrocytes in vitro. In rat models of cerebral ischemia, we observed increased glial fibrillary acidic protein (GFAP) expression, reflecting astrogliosis, and increased lactate levels in the ischemic brain region. Lactate upregulated GFAP and SRY-box transcription factor 9 (SOX9) expression and activated Akt and signal transducer and activator of transcription 3 (STAT3) signaling pathways in astrocytes cultured under oxygen-glucose deprivation (OGD); these effects were abrogated upon monocarboxylate transporter 1 (MCT1) knockdown. RNA-Seq analysis revealed 221 differentially expressed genes (DEGs) between lactate-treated and untreated astrocytes. Genes upregulated by lactate treatment included those regulating astrogliosis and axon guidance. Consistently, lactate-treated astrocytes induced neuronal outgrowth upon coculture. Our results suggest that lactate promotes reactive astrogliosis and confers axon guidance potential to astrocytes under OGD.

Keywords: astrocytes; astrogliosis; axon guidance; cerebral ischemia; lactate.