Ischemic stroke (IS) is a detrimental neurological disease with limited treatments options. It has been challenging to define the roles of brain cell subsets in IS onset and progression due to cellular heterogeneity in the CNS. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell populations in the mouse model of MCAO (middle cerebral artery occlusion). We identified 17 principal brain clusters with cell-type specific gene expression patterns as well as specific cell subpopulations and their functions in various pathways. The CNS inflammation triggered upregulation of key cell type-specific genes unpublished before. Notably, microglia displayed a cell differentiation diversity after stroke among its five distinct subtypes. Importantly, we found the potential trajectory branches of the monocytes/macrophage’s subsets. Finally, we also identified distinct subclusters among brain vasculature cells, ependymal cells and other glia cells. Overall, scRNA-seq revealed the precise transcriptional changes during neuroinflammation at the single-cell level, opening up a new field for exploration of the disease mechanisms and drug discovery in stroke based on the cell-subtype specific molecules.

The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.

No abstract

Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran’s Q, I2 test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08–2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.