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Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice [scRNA-Seq]

ABSTRACT: Wnt signaling is critical for blood-brain barrier function, neuronal survival and adult neurogenesis, yet Wnt proteins are poorly suited as therapeutics for stroke due to production and pharmacokinetic challenges. Here, we show that R-spondins (RSPOs), a family of easily produced and secreted proteins capable of robustly augmenting Wnt signaling, are widely expressed in adult mouse brain and upregulated upon ischemia and reperfusion injury. Neutralizing endogenous RSPOs with the soluble ectodomains of their membrane receptors LGR5, ZNRF3 and RNF43 increased cerebral infarction in a murine stroke model. Conversely, systemic administration of RSPOs substantially reduced cerebral infarction and improved neurological outcomes. The neuroprotective effects of RSPOs were dependent on LGR4/ZNRF3-mediated augmentation of canonical Wnt/-catenin signaling in endothelial and neuronal cells, which in turn promoted blood-brain barrier integrity, neuronal PDGF-CC expression and survival. Further, RSPOs promotes the proliferation and expansion of neural stem/progenitor cells and post-stroke neurogenesis. Thus, we identify a previously unknown neuroprotective and pro-neurogenic mechanism and describe the therapeutic potential of recombinant RSPOs in ischemic stroke.

ORGANISM(S): Mus musculus

PROVIDER: GSE159454 | GEO | 2023/10/07

REPOSITORIES: GEO

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Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.

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Therapeutic use of R-spondins to augment the cerebrovascular and neuronal Wnt signaling and improve stroke outcome in mice [scRNA-Seq]

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