|Titel:||Role of neuroblast-derived signals in post-stroke neurovascular remodeling||Sprache:||Englisch||Autor*in:||Lengning, Tamal Bhadra||Schlagwörter:||stroke; neurogenesis; angiogenesis||Erscheinungsdatum:||2022||Tag der mündlichen Prüfung:||2023-03-24||Zusammenfassung:||
Stroke is one of the leading causes of death and disability yet remains without an effective treatment. Stroke itself induces a wide range of repair mechanisms that allow for limited recovery, including angiogenesis and neurogenesis. Previous studies have demonstrated that neuroblasts migrate to sites of ischemic injury and preferentially associate with the angiogenic vasculature. The signaling systems underlying neuroblast-vessel communication are incompletely understood. A better understanding of these endogenous repair mechanisms may lead to novel therapeutic approaches. To this end, previous studies in the Carmichael laboratory, using genome-wide expression profiling studies, identified the post-stroke neurovascular interactome. In this study, we selected four genes dysregulated in stroke-responsive neuroblasts for mechanistic gain- and loss-of-function studies: CCL9, WNT7A, GAS6 and PTN. We hypothesized that candidate gene overexpression will enhance the angiogenic and neurogenic response, while gene knockdown will impair post-stroke neurogenesis and angiogenesis. To test this hypothesis, we employed lentiviral gene overexpression or miRNA mediated gene knockdown in a photothrombotic model of ischemic stroke and quantified the number of proliferating endothelial cells (ECs), peri-infarct vessel density and the number of newborn neurons. We found CCL9 and WNT7A overexpression to significantly increase EC proliferation after stroke, while knockdown of CCL9 reduced the number of proliferating ECs. Overexpression of CCL9 increased peri-infarct vessel density, while loss of CCL9 lead to a significant reduction in vessel density. Loss of PTN increased vessel density without showing any effects on EC proliferation. Both WNT7A as well as CCL9 overexpression increased post-stroke neurogenesis (NeuN+/EdU+ cells) while loss of CCL9, WNT7A and PTN impaired the neurogenic response. In a second study, we delivered CCL9 protein through a hydrogel sitting in the infarct cavity in a MCAo model of ischemic stroke and also found EC proliferation to be enhanced. Taken together, we identified several novel regulators of post-stroke neurovascular remodeling. We found CCL9 to produce the most robust effects on neurovascular remodeling, which we were able to reproduce in two different models of ischemic stroke with two different delivery approaches.
Carmichael, Stanley Thomas
|Enthalten in den Sammlungen:||Elektronische Dissertationen und Habilitationen|
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geprüft am 09.06.2023
geprüft am 09.06.2023