Stroke is the leading cause of adult disability. Stroke induces a neural stem cell/ precursor response: newly born, immature neurons (neuroblasts) migrate to the area of injury and differentiate into more mature neurons. This neuroblast response after stroke may offer a strategy of cell replacement if properly harnessed. The goal of this application is to define the cellular signals that stimulate neuroblast migration and localization to peri-infarct tissue in the brain after stroke. Neuronal differentiation normally occurs in the adult in close association with vascular endothelial cells, an environment termed the neurovascular niche. Stroke induces profound changes in the vasculature around the infarct. This application will build on preliminary data that shows that newly born neuroblasts form a tight spatial relationship with the vascular endothelium in peri-infarct cortex, to test the hypothesis that stroke induces neuroblast migration and localization by creating a novel neurovascular environment or niche surrounding the infarct. The conjoint signaling molecules between neuroblasts and endothelial cells in this niche will be identified, with reference to vascular growth factors and cell guidance molecules, by laser capture of neuroblasts and their associated endothelial cells. Gain and loss of function experiments within these signaling systems will then be used to identify their mechanistic roles in post-stroke neurogenesis. Preliminary data shows that systemic administration of candidate vascular growth factors and their antagonists selectively increase or decrease post-stroke neurogenesis, through an opened blood brain barrier in peri-infarct cortex. This ability to selectively augment or diminish post-stroke neurogenesis will be used to determine the long-term survival and degree of integration of newly born neurons after stroke, and the effect of post-stroke neurogenesis on behavioral recovery. Altogether, this application will apply mechanistic experiments to define the molecular signaling, anatomical organization and effect on recovery of a novel cellular environment for repair after stroke?a neurovascular niche that supports neurogenesis in peri-infarct cortex. Relevance to Public Health: These studies will define the mechanisms of a neural stem cell response after stroke, which provides new neurons in areas in which cells have been lost from stroke damage. An understanding of the molecules that promote this neural stem cell response after stroke will help develop novel therapies to promote replacement of brain cells in this disease. ? ? ?
| Kokaia, Zaal; Llorente, Irene L; Carmichael, S Thomas (2018) Customized Brain Cells for Stroke Patients Using Pluripotent Stem Cells. Stroke 49:1091-1098 |
| Carmichael, S Thomas; Kathirvelu, Balachandar; Schweppe, Catherine A et al. (2017) Molecular, cellular and functional events in axonal sprouting after stroke. Exp Neurol 287:384-394 |
| Carmichael, S Thomas (2016) Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol 79:895-906 |
| Carmichael, S Thomas (2016) The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative. Neurotherapeutics 13:348-59 |
| Dobkin, Bruce H; Carmichael, S Thomas (2016) The Specific Requirements of Neural Repair Trials for Stroke. Neurorehabil Neural Repair 30:470-8 |
| Prakash, Roshini; Carmichael, S Thomas (2015) Blood-brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury. Curr Opin Neurol 28:556-64 |
| López-Valdés, Héctor E; Clarkson, Andrew N; Ao, Yan et al. (2014) Memantine enhances recovery from stroke. Stroke 45:2093-2100 |
| Gleichman, Amy J; Carmichael, S Thomas (2014) Astrocytic therapies for neuronal repair in stroke. Neurosci Lett 565:47-52 |
| Sozmen, Elif G; Hinman, Jason D; Carmichael, S Thomas (2012) Models that matter: white matter stroke models. Neurotherapeutics 9:349-58 |
| Carmichael, S Thomas (2010) Translating the frontiers of brain repair to treatments: starting not to break the rules. Neurobiol Dis 37:237-42 |
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