One of the areas that I likely will be getting involved in over the coming couple of months is that of studying neural progenitor cells in an in vitro model of neuro-regenerative therapy. One of the more interesting areas of stem cell research is in regenerative therapy of the central nervous system (CNS) following injuries, ischemia, or degenerative diseases. Some early experiments have shown promise in restoring neurological function for such cases, but the mechanisms underlying restorative neurogenesis are poorly understood. Case in point: yesterday, I attended a lecture on campus by a faculty member from Cornell’s medical college in NYC, who has been studying novel ways to identify, understand and treat ischemic foci following epileptic seizures – and while she sees a lot of hope for transplanted neural progenitor cells in such therapies, she (and other neurologists) really have little understanding of how these cells migrate in vivo, survive, differentiate and establish new connections to replace those lost.
So I thought I’d do a little literature review, and came across a paper that really seems to summarize this topic quite well: Neurogenesis in the Adult Ischemic Brain: Generation, Migration, Survival, and Restorative Therapy.
The paper discusses a couple topics that I’m not planning to focus on, but to mention briefly, Zhang et al. describe what’s known about cell proliferation and population maintenance in the subventricular zone (SVZ).
More interesting (to me) is their discussion on migration of neuroblasts. For instance, it’s known that focal cerebral ischemia transiently increases symmetric division of neural progenitor cells, and neuroblasts migrate toward ischemic striatum in a chainlike structure. Then, when migrating neuroblasts reach the ischemic boundary, they form clusters and disperse. whether astrocytes regulate this process is one of their major questions, but the data thus far suggests that the astrocytes merely form a physical barrier prior to ischemic stroke, and are not involved in guiding neuroblasts in regenerative neurogenesis.
Another problem is trying to understand what determinants influence migration to ischemic neocortex and striatum regions – this seems to be a very complex problem, with a variety of factors acting in concert to orchestrate pathfinding.
Promising work appears to relate the survival and integration of neuroblasts as new neurons in neurogenesis, to a confluence of angiogenic vessels. I.e. more oxygen-rich hemoglobin helps restore tissues damaged by ischemia; that makes sense, but it goes further: newly formed endothelial cells apparently produce neurotrophic factors, including brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) (Shen et al., 2004). Similar work indicates related roles for Erythropoietin (EPO), Nitric Oxide/cGMP signaling, EGF, IGF-1, and PI(3)K/Akt signaling.
But are these angiogenic signals the whole picture? What signals act as guidance molecules in aiding neuroblasts to find these “vascular niches?” And how can we “prime” neural progenitor cells, or pharmacologically enhance their role in repair of neuronal tissue damaged by ischemia, etc.?
- Neurogenesis in the Adult Ischemic Brain: Generation, Migration, Survival, and Restorative Therapy. Zhang RL, Zhang ZG, Chopp M. Neuroscientist. 2005 Oct; 11(5):408-16.
- Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S. Science. 2004 May 28; 304(5675):1338-40.