Introduction: Wnt/ beta-catenin signaling has been identified as an essential component of adult neurogenesis within the hippocampus. Its role within the adult Subventricular zone, SVZ, is less well understood, as is its role in the context of post-stroke neurogenesis. With this work we aim to 1) determine the presence of active Wnt/ beta-catenin signaling following experimental focal cerebral ischemia 2) identify the cell types that it is upregulated by 3) establish its effects on neurogenesis, regeneration and recovery following stroke through administering a liposomal Wnt-3a protein preparation directly into the brain parenchyma.
Methods: - Axin 2 +/- male mice, reporter for Wnt/ beta-catenin signaling, were subjected to 30 min MCAO. Activation of the pathway was determined via immunohistochemistry.
- C57/ Bl6 male mice were subjected to 30 min of MCAO. Wnt-3a liposomes, made and in vitro tested in the lab, were injected intraparenchymally at 2, 4 and 6 days post-MCAO. Behavior tests, horizontal ladder test and adhesive removal test, were performed at -2 days and 1, 2, 3 and 4 weeks post stroke.
Results: we have determined that:
- Wnt/ beta-catenin signaling is upregulated at 1, 3 and 5 days post_MCAO in mice
- the main site is the Subventricular zone, SVZ, a site of endogenous neurogenesis, however it is also active in reactive astrocytes in the penumbra and within mature neurons
- intraparechymal injection of Wnt3a liposomes, prepared in the lab, robustly activates the pathway both in vitro and in vivo and enhances the endogenous neurogenesis
- functional recovery, following repetitive intraparecymal Wnt-3a liposome injection, is also enhanced, as determined by behavior tests
Conclusions: The Wnt/ beta catenin pathway is active within the adult Subventricular zone post-stroke, as well as in other cell types. Further activating the pathway through intraparenchymal Wnt-3a liposomal injection has a pro-neurogenic effect and improves function after MCAO.
Patient Care: - currently there is no approved regenerative therapy post-stroke
- Wnt-3a liposomes could potentially be used as a post-stroke therapy promoting neurogenesis, regeneration and functional recovery
Learning Objectives: - to demonstrate the activity of a very important developmental pathway in the context of stroke
- to show the effect of activating the pathway in vivo following experimental cerebral ischemia