NEUROGENESIS AFTER STROKE

Stroke signals to stem cell populations in the adult brain to divide, and to send immature neurons to areas of damage. This process is termed post-stroke neurogenesis. Neurogenesis normally occurs in two sites in the adult brain, the subventricular zone (SVZ, perhaps more properly called the subependymal zone) and the subgranular zone in the hippocampus. For a relationship to human stroke, the most meaningful site for post-stroke neurogenesis is in the SVZ. This is because human stroke rarely occurs in the hippocampus, and most acute stroke deficits relate to sensory, motor, language or attentional functions in the cerebral hemisphere or its descending connections and not to hippocampal function. Thus an understanding of how stem cells in the SVZ sense and respond to stroke may provide information that would lead to a process that could boost post-stroke neurogenesis, new neuron production, and recovery.

The SVZ contains slowly dividing and multipotent neural progenitors, which can produce astrocytes, oligodendrocytes and neurons; more rapidly dividing cells that are more closely committed to neuronal lineages in the normal adult brain; and immature neurons (or neuroblasts).  All three cell types respond to a stroke in the striatum, which is close to the SVZ.  For a post-stroke neurogenesis to be relevant to humans, a stroke must activate neurogenesis from sites that are further removed from the SVZ than is the rodent striatum. This is because strokes in the mouse or rat striatum that activate post-stroke neurogenesis are literally only tens of microns away from the SVZ. However, the range of human stroke topography is such that very few strokes are that close to the striatum. We first set out to determine if strokes that are still within the major vascular supply for human stroke locations (the middle cerebral artery, MCA) but are as distant as possible from the SVZ would still induce post-stroke neurogenesis. Stroke produced in the somatosensory whisker representation of the mouse (termed the "barrel field") are as far from the SVZ as can be produced with an MCA stroke. However, this stroke still produces a robust process of post-stroke neurogenesis.

DCX-RFP stroke

A closer examination of the environment that attracts the long-distance migration of immature neurons shows that these cells localize to angiogenic blood vessels within the cortical tissue adjacent to the stroke, termed the peri-infarct cortex.  This association of newly born, immature neurons and angiogenic blood vessels defines a neurovascular niche for post-stroke neurogenesis. Other investigators have also identified such a neurovascular association in post-stroke neurogenesis. The header photo for this page shows a blood vessel in peri-infarct cortex (green), with newly dividing endothelial cells (BrdU label, purple) and adjacent neuroblasts (red, doublecortin).

Stroke interacts with the SVZ through several signaling systems. We have shown that three cytokine/chemokine signaling systems promote post-stroke neurogenesis and long distance migration of neuroblasts to areas of damage. Endogenous erythropoietin, induced by stroke, increases the number of neuroblasts that migrate to peri-infarct cortex (Tsai et al.). The chemokine stromal derived factor 1 (SDF1) is induced in peri-infarct blood vessels and serves as a tropic signal for migrating neuroblasts to localize to this area of damage. Angiopoietin 1 serves a similar role. Within the neuroblasts, the PI3 kinase/Akt pathway plays an important role in neuroblast function. Mutations that produce constitutive activation of the Akt pathway, such as PTEN deletion, induce a robust increase in post-stroke neurogenesis.

Current projects in the Carmichael lab are defining the cellular signaling systems that communicate between endothelial cells and neuroblasts in this neurovascular niche, and the role of other cells in the niche, including inflammatory cells.