Abstract WP348: Astrocyte Reaction After Ischemic Stroke in Nonhuman Primate

Abstract

In the mammalian central nervous system, gliogenesis and neurogenesis constitutively occurs in the subventricular zone (SVZ) and the hippocampus albeit on a much lower scale in comparison to the other organs. In response to stroke and presumably as an endogenous mechanism of brain self repair, the neural precursors located in the SVZ and the hippocampus are induced to proliferate and migrate towards stroke-damaged tissue. This innate neural reaction in adult brain may represent a mechanism of neuroplasticity and structural remodeling that leads to functional recovery. The rodent animal model of ischemic stroke (IS) showed a clear and pronounced neurogenesis and gliogenesis. However, to date little is known about this innate response in human and nonhuman primates to IS. We have developed a nonhuman primate model of IS with well-defined anatomical infarct lesions and motor behavioral deficit. After a small craniotomy, the dura was opened and with microsurgical technique and the M3 segment of the middle cerebral artery was occluded for 90 minutes followed by reperfusion. Animals with IS showed significant (p<0.005) motor deficit in right hand. To label endogenous neural precursors undergoing cell proliferation in vivo we injected all animals with the S-phase marker 5-bromo-2-deoxyuridine (BrdU). Postmortem analysis demonstrated significant increase of GFAP+ astrocytes (P<0.0001) in the infarct area. These astrocytes exhibited unique re-organization around the infarct zone and expressed various types of morphologies and phenotypes. Less than 1% incorporated BrdU. Sixty-five % of astrocytes with elongated processes oriented toward the IS co-expressed vimentin while tissue from control animals expressed no vimentin. Approximately 35% of astrocytes co-expressed Sox-2, while control animals showed about 4% in the same area of the cortex. Both vimentin and Sox-2 are markers for neural stem cells. These data suggests that astrocytes may be more heterogeneous than previously thought and may undertake various roles in response to IS. A subpopulation of astrocytes may be reprogrammed to an early developmental stage under IS conditions to promote tissue repair and homeostasis.