Spatiotemporal Transcriptomic Map of Experimental Ischemic Brain Injury

Spatiotemporal Transcriptomic Map of Experimental Ischemic Brain Injury

Abstract
Ischemic brain injury (stroke) is a devastating neurological disease, affecting nearly 12 million people per year worldwide. Owing to limited treatment strategies, a vast proportion of patients dies or suffers of long-term disability, which represents a major health care and economic burden. The unfavorable outcome is affected by disease complexity, involving numbers of cell types intertwined in a large interaction network. Moreover, stroke pathology shows a strong spatiotemporal character, with a dominant role of lesion epicenter and surrounding penumbra, which function and cell type composition undergo dramatic changes during first days after the injury. To untangle the complexity of the stroke pathobiology, we characterized gene expression landscape of experimental ischemic brain injury with spatial and single-cell transcriptomics. Using mouse model of permanent middle-cerebral artery occlusion, mimicking the permanent clogging of major cerebral artery, we profiled the injured brain at 1, 3 and 7 days after the ischemic stroke. We documented severe disruption of cortical gene expression landscape, with a prominent cell death and inflammatory response having different cell components and spatial localization in time. Focused on glia cells, a prominent element of the response, we uncovered a rise of their reactive populations, with strong resemblance to their counterparts identified in neurodegenerative diseases. Lastly, we characterized ischemia-induced populations of oligodendrocytes, contesting the long-term dogma of their passive role with limited responsiveness to pathogenic stimuli. To sum up, we present a landmark spatial transcriptomic dataset of experimental ischemic stroke, providing unique insight on the processes and cell types involved in pathogenesis of ischemia with spatial, temporal and single-cell resolution. We hope that this resource will stimulate further studies, leading to advances in search for new therapy of the ischemic brain injury in the near future.