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Bioluminescence imaging of stroke-induced endogenous neural stem cell response

Vandeputte, Caroline; Reumers, Veerle; Aelvoet, Sarah-Ann; Thiry, Irina; De Swaef, Sylvie; Van den Haute, Chris; Pascual-Brazo, Jesus; Farr, Tracy D.; Vande Velde, Greetje; Hoehn, Mathias; Himmelreich, Uwe; Van Laere, Koen; Debyser, Zeger; Gijsbers, Rik; Baekelandt, Veerle

Authors

Caroline Vandeputte

Veerle Reumers

Sarah-Ann Aelvoet

Irina Thiry

Sylvie De Swaef

Chris Van den Haute

Jesus Pascual-Brazo

Tracy D. Farr

Greetje Vande Velde

Mathias Hoehn

Uwe Himmelreich

Koen Van Laere

Zeger Debyser

Rik Gijsbers

Veerle Baekelandt



Abstract

Brain injury following stroke affects neurogenesis in the adult mammalian brain. However, a complete under¬standing of the origin and fate of the endogenous neural stem cells (eNSCs) in vivo is missing. Tools and technol¬ogy that allow non-invasive imaging and tracking of eNSCs in living animals will help to overcome this hurdle. In this study, we aimed to monitor eNSCs in a photothrombotic (PT) stroke model using in vivo bioluminescence imaging (BLI). In a first strategy, inducible transgenic mice expressing firefly luciferase (Fluc) in the eNSCs were generated. In animals that received stroke, an increased BLI signal originating from the infarct region was ob¬served. However, due to histological limitations, the identity and exact origin of cells contributing to the in¬creased BLI signal could not be revealed. To overcome this limitation, we developed an alternative strategy employing stereotactic injection of conditional lentiviral vectors (Cre-Flex LVs) encoding Fluc and eGFP in the subventricular zone (SVZ) of Nestin-Cre transgenic mice, thereby specifically labeling the eNSCs. Upon induction of stroke, increased eNSC proliferation resulted in a significant increase in BLI signal between 2 days and 2 weeks after stroke, decreasing after 3 months. Additionally, the BLI signal relocalized from the SVZ towards the infarct region during the 2 weeks following stroke. Histological analysis at 90 days post stroke showed that in the peri-infarct area, 36% of labeled eNSC progeny differentiated into astrocytes, while 21% differentiated into mature neu¬rons. In conclusion, we developed and validated a novel imaging technique that unequivocally demonstrates that nestin+ eNSCs originating from the SVZ respond to stroke injury by increased proliferation, migration towards the infarct region and differentiation into both astrocytes and neurons. In addition, this new approach allows non-invasive and specific monitoring of eNSCs overtime, opening perspectives for preclinical evaluation of can¬didate stroke therapeutics.

Journal Article Type Article
Publication Date Sep 1, 2014
Journal Neurobiology of Disease
Print ISSN 0969-9961
Electronic ISSN 1095-953X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 69
APA6 Citation Vandeputte, C., Reumers, V., Aelvoet, S., Thiry, I., De Swaef, S., Van den Haute, C., …Baekelandt, V. (2014). Bioluminescence imaging of stroke-induced endogenous neural stem cell response. Neurobiology of Disease, 69, doi:10.1016/j.nbd.2014.05.014
DOI https://doi.org/10.1016/j.nbd.2014.05.014
Keywords Bioluminescence imaging; Cre-Flex lentiviral vector; Endogenous neural stem cells; Nestin-Cre mice;
Stroke
Publisher URL http://www.sciencedirect.com/science/article/pii/S0969996114001326
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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