SorCS2 is an intracellular sorting receptor of the VPS10P domain receptor gene family recently implicated in oxidative stress response. Here, we interrogated the relevance of stress‐related activities of SorCS2 in the brain by exploring its role in ischemic stroke in mouse models and in patients. Although primarily seen in neurons in the healthy brain, expression of SorCS2 was massively induced in astrocytes surrounding the ischemic core in mice following stroke. Post‐stroke induction was likely a result of increased levels of transforming growth factor β1 in damaged brain tissue, inducing Sorcs2 gene transcription in astrocytes but not neurons. Induced astrocytic expression of SorCS2 was also seen in stroke patients, substantiating the clinical relevance of this observation. In astrocytes in vitro and in the mouse brain in vivo, SorCS2 specifically controlled release of endostatin, a factor linked to post‐stroke angiogenesis. The ability of astrocytes to release endostatin acutely after stroke was lost in mice deficient for SorCS2, resulting in a blunted endostatin response which coincided with impaired vascularization of the ischemic brain. Our findings identified activated astrocytes as a source for endostatin in modulation of post‐stroke angiogenesis, and the importance of the sorting receptor SorCS2 in this brain stress response.
clear, predictable, and irreversible criteria, which can be used as a substitute for a more severe experimental outcome such as extreme suffering or death. Systematic implementation of humane endpoints can prevent or reduce pain and/or suffering whilst still meeting experimental objectives (Nemzek et al., 2004).Thus, application of humane endpoints is a key component of refining studies to comply with 3R principles. In models of acute disease, death may occur within hours following an experimental intervention, which requires both intensive follow-up and consis- IntroductionIn experimental mouse studies an important challenge for researchers is to identify an endpoint by which the experiment shall be terminated in order to minimize unnecessary suffering of animals without compromising the quality of the experimental data. To systematically address this challenge, the concept of humane endpoints was introduced almost 20 years ago in Europe (OECD, 2000). The application of humane endpoints describes the use of
Background: Prediction of post-stroke outcome using the degree of subacute deficit or magnetic resonance imaging is well studied in humans. While mice are the most commonly used animals in preclinical stroke research, systematic analysis of outcome predictors is lacking. Methods: Data from 13 studies that included 45 min of middle cerebral artery occlusion on 148 mice were pooled. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were co-registered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. Results: We detected both a subacute and residual motor-functional deficit after stroke in mice. Different functional severity grades and recovery trajectories could be observed. In mice with small cortical lesions, lesion volume was the best predictor of the subacute deficit. The residual deficit could be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increased prediction accuracy. A subset of anatomical regions within the ischemic lesion had particular impact on the prediction of long-term outcome. Prediction accuracy depended on the degree of functional impairment. Conclusions: For the first time, we identified and characterized predictors of post-stroke outcome in a large cohort of mice and found strong concordance with clinical data. These results are discussed in light of study design and imaging limitations. In the future, using outcome prediction can improve the design of preclinical studies and guide intervention decisions.
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