| This dissertation is a contribution to our understanding of the identity of neural stem cells and their role in promoting restorative growth in the mammalian brain. Evidence is presented to show that cells of the ependymal layer adjacent to the forebrain lateral ventricles act as neural stem cells (NSCs) in the adult rat and can be activated to divide by a combination of chemical injury and growth factor infusion given to reverse the effects of that injury. Markers of asymmetric cell division (ACD), a characteristic of stem cells in a variety of model systems, are expressed asymmetrically in the ependymal layer but not in the underlying subventricular zone (SVZ). When the brain is treated with a combination of 6-hydroxydopamine (6-OHDA) and systemic delivery of transforming growth factor-alpha (TGFalpha) ependymal cells divide asymmetrically and transfer progeny into the SVZ. SVZ cells then divide as transit-amplifying cells and probably contribute their progeny to the neuronal lineage, leading to some recovery of structure as well as function. The stem cells in the ependymal layer may have been missed in many previous studies because they are usually quiescent and divide only in response to strong stimuli. When TGFalpha is given following a middle cerebral arterial occlusion (MCAO) stroke injury, a similar pattern of ependymal and SVZ proliferation results, apparently leading to adult neurogenesis and behavioral improvement. Delivery of pegylated-TGFalpha by an intranasal route of administration following MCAO is also shown to have therapeutic potential. |
