White Matter Stroke and Repair
Up to 30% of all strokes in humans occur as infarcts in the white matter. In addition, white matter stroke accumulate and expand radially, leading to more confluent white matter lesions and vascular dementia. There have been few studies of the molecular and cellular mechanisms of white matter stroke damage and repair or of mechanisms of progression of lesions in vascular dementia and of repair. The basic research in this area has been limited because of the difficulty in establishing an animal model of subcortical white matter stroke in the rodent. We have developed two models of subcortical/white matter stroke in the mouse. Both models utilize a selective eNOS inhibitor to cause vasoconstriction in the subcortical white matter that corresponds to the most frequently occurring lesion site in humans. This is damage in the mouse below the forelimb motor cortex. The two stroke differ in size, with one being a smaller and more localized stroke and the other a larger and more confluent stroke. The larger stroke model reflects the damage seen in vascular dementia.
The mall stroke model shows a focal white matter stroke and in comparison to a human MRI of white matter stroke in an early stage of vascular dementia. This model is published:
A white matter stroke model in the mouse: axonal damage, progenitor responses and MRI correlates. Sozmen EG, Kolekar A, Havton LA, Carmichael ST. J Neurosci Methods. 2009. 180:261-72. doi: 10.1016/j.jneumeth.2009
Age-dependent exacerbation of white matter stroke outcomes: a role for oxidative damage and inflammatory mediators. Rosenzweig S, Carmichael ST. Stroke. 2013 Sep;44(9):2579-86. doi: 10.1161/STROKEAHA.113.001796.
A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology. Nunez S, Doroudchi MM, Gleichman AJ, Ng KL, Llorente IL, Sozmen EG, Carmichael ST, Hinman JD. J Vis Exp. 2016 Mar 17;(109):53404. doi: 10.3791/53404.
Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice. Sozmen EG, Rosenzweig S, Llorente IL, DiTullio DJ, Machnicki M, Vinters HV, Havton LA, Giger RJ, Hinman JD, Carmichael ST. Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8453-E8462. doi: 10.1073/pnas.1615322113.
White Matter Stroke Induces a Unique Oligo-Astrocyte Niche That Inhibits Recovery. Sozmen EG, DiTullio DJ, Rosenzweig S, Hinman JD, Bridges SP, Marin MA, Kawaguchi R, Coppola G, Carmichael ST. J Neurosci. 2019 Nov 20;39(47):9343-9359. doi: 10.1523/JNEUROSCI.0103-19.2019
The larger white matter stroke has these features on MRI, as compared to human vascular dementia:
This model has also been published. In this study, published in Science Translational Medicine, a new stem cell therapy was developed to repair the brain in white matter stroke/vascular dementia.
Ongoing projects in the lab are exploring how the cells of the white matter respond to ischemia in vascular dementia, and either die or exhibit regeneration. These cells form a specific microenvironment termed the neurovascular niche. By studying the cell-cell signaling systems that are active in the neurovascular niche during vascular dementia, processes that promote resilience or repair can be identified.