Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke
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PROVIDER: PRJNA886450 | ENA |
REPOSITORIES: ENA
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Project description:Ischemic stroke causes extensive neuronal cell death. Antithrombotic agents and rehabilitation are the primary treatment options but have limited efficacy. Therefore, to achieve radical neurological improvement, practical neuroregenerative technologies must be developed. Recently, direct chemical reprogramming using small molecules to transdifferentiate somatic cells into neurons has garnered much attention. We investigated the possibility of applying this technology for the treatment of ischemic stroke. During the acute phase of ischemic stroke, circulating monocytes increase chemotaxis and accumulate in the infarct area through the disrupted blood-brain barrier, where they differentiate into macrophages involved in inflammation and remodeling. Direct reprogramming of these monocyte-derived macrophages into neuronal cells in vivo is theoretically possible with the administration of small-molecule drugs. However, the efficacy of this neuroregenerative therapy cannot be verified because the optimal chemical compounds that convert macrophages into neurons have not yet been identified.
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Project description:Stroke remains a major leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures of ischemic stroke within the hyper-acute phase of the disease is still of primary interest for a real translational research on stroke diagnosis, prognosis and treatment. High-throughput - omics technologies are enabling large-scale studies on stroke pathology at different molecular levels. Data integration resulting from these -omics approaches is becoming crucial to unravel the interactions among all different molecular elements and highly contribute to interpret all findings in a complex biological context. Here, we have used advanced data integration methods for multi-level joint analysis of transcriptomics and proteomics datasets depicted from the mouse brain 2h after cerebral ischemia. By modeling network-like correlation structures, we identified a set of differentially expressed genes and proteins by ischemia with a relevant association in stroke pathology. The ischemia-induced deregulation of 10 of these inter-correlated elements was successfully verified in a new cohort of ischemic mice, and changes in their expression pattern were also evaluated at a later time-point after cerebral ischemia. Of those, CLDN20, GADD45G, RGS2, BAG5 and CTNND2 were highlighted and evaluated as potential blood biomarkers of cerebral ischemia in blood samples from ischemic and sham-control mice and from ischemic strokes and other patients presenting stroke-mimicking conditions. Our findings indicated that CTNND2 and GADD45G levels in blood within the first hours after ischemic stroke might be potentially useful to discriminate ischemic strokes from mimics and to predict patients’ poor outcome after stroke, respectively. In summary, we have here used for the first time an integrative approach to elucidate by means of biostatistical tools key elements of the initial stages of the stroke pathophysiology, highlighting new outstanding proteins that might be further considered as blood biomarkers of ischemic stroke.
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