Stroke constitutes the third leading cause of death in the world and is the number one cause of sensory, motor and cognitive dysfunction in adults, with few effective therapies available. Recent studies have shown, however, that the adult CNS has an innate, albeit limited, ability to repair itself through the migration of endogenous neural stem/progenitor cells (NSPCs) from the subventricular zone (SVZ) to the site of injury, which have the capacity of forming mature neuronal cell types. However, this repair mechanism is not currently well understood, and is hindered by low survival of newly generated cells in the ischemic environment. Here, we investigate the role of resident and blood borne microglia/macrophages in initiating the neurogenic repair process by promoting migration of endogenous NSPCs to peri-infarct regions by release of a specific chemotactic cytokine, Stromal Derived Factor-1 alpha (SDF-1alpha). Our preliminary studies show that through secretion of SDF-1 alpha by microglial cells acutely, the innate immune response is critical in promoting the migration of NSPCs to peri-infarct sites, linking the immune response post-ischemia to the neural repair mechanisms that occur through the process of adult neurogenesis. Conversely, in the chronic stages post ischemia, our initial studies also show that SDF-1 can be proteolytically truncated into a neurotoxic form after ischemia, possibly by matrix metalloproteinase activity. These findings reveal a potential novel mechanism of NSPC cell death after ischemia that is induced by the truncation of SDF-1 due to factors within the injured neurovascular niche, and is consistent with the significant NSPC cell death hindering the endogenous neurogenic repair process. We propose, therefore, that the immune response coupled to the release of SDF-1 by microglia/macrophages can regulate both (1) the migration and differentiation of NSPCs through a SDF- 1/CXCR4 dependent pathway in the acute period post-ischemia, as well as (2) initiate NSPC cell death through truncated SDF-1 acting through a CXCR3 dependent pathway in the chronic phase, mediating cell death. These diverging roles of SDF-1 form a time-dependent axis of SDF-1 activity possibly regulated by the presence of MMP proteases in the ischemic neurovascular niche, and the indepth investigation of both MMP activity and SDF-1 alpha truncation will be critical in enhancing NSPC survival, a central theme for the current study. Careful regulation of this immune response and prevention of SDF- 1 alpha truncation post-ischemia through interventional strategies will be carried out in this study to assess novel therapies for neural stem cell survival and maturation of NSPCs into functional neurons that can improve neurological recovery post-ischemic insult.

Public Health Relevance

Stroke constitutes the third leading cause of death and is the number one cause of neurological dysfunction in the developed world. To ameliorate the severe motor, sensory and cognitive deficits suffered after stroke, this study seeks to enhance the process of endogenous adult neurogenesis in the brain by introducing interventional strategies to enhance neural stem cell survival, maturation and differentiation into functional neurons that can support injured neurons or integrate with existing neuronal networks to improve neurological recovery after ischemia.

Agency
National Institute of Health (NIH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS070589-04
Application #
8693031
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Bosetti, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
None
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115