Intravenous administration of human umbilical tissue-derived cells improves neurological function in aged rats after embolic stroke.

Intravenous administration of human umbilical tissue-derived cells (hUTC) improves neurological function in young adult rats after stroke. However, stroke is a major cause of death and disability in the aged population, with the majority of stroke patients 65 years and older. The present study investigated the effect of hUTC on aged rats after embolic stroke. Rats at the age of 18-20 months were subjected to embolic middle cerebral artery (MCA) occlusion. Two groups of eight animals each were compared. The investigational group was injected intravenously with 1×10(7) cells/kg in serum-free culture medium (vehicle) 24 h after stroke onset, and the control group was treated with vehicle only at the same time poststroke. Intravenous administration of hUTC significantly improved neurological functional recovery without reducing infarct volume compared to vehicle-treated aged rats. Additionally, hUTC treatment significantly enhanced synaptogenesis and vessel density in the ischemic boundary zone (IBZ). Moreover, hUTC treatment resulted in a trend toward increased progenitor cell proliferation in the subventricular zone (SVZ) compared to vehicle-treated aged rats. Intravenous administration of hUTC improved functional recovery in aged rats after stroke. The enhancement of synaptogenesis and vessel density may contribute to the beneficial effects of hUTC in the treatment of stroke in the aged animal.

Different routes of administration of human umbilical tissue-derived cells improve functional recovery in the rat after focal cerebral ischemia.

Human umbilical tissue-derived cells (hUTC) are a potential neurorestorative candidate for stroke treatment. Here, we test the effects of hUTC treatment in a rat model of stroke via various routes of administration. Rats were treated with hUTC or phosphate-buffered saline (PBS) via different routes including intraarterial (IA), intravenous (IV), intra-cisterna magna (ICM), lumber intrathecal (IT), or intracerebral injection (IC) at 24h after stroke onset. Treatment with hUTC via IV and IC route led to significant functional improvements starting at day 14, which persisted to day 60 compared with respective PBS-treated rats. HUTC administered via IA, ICM, and IT significantly improved neurological functional recovery starting at day 14 and persisted up to day 49 compared with PBS-treated rats. Although IA administration resulted in the highest donor cell number detected within the ischemic brain compared to the other routes, hUTC treatments significantly increased ipsilateral bromodeoxyuridine incorporating subventricular zone (SVZ) cells and vascular density in the ischemic boundary compared with PBS-treated rats regardless of the route of administration. While rats received hUTC treatment via IA, IV, IC, and ICM routes showed greater synaptophysin immunoreactivity, significant reductions in TUNEL-positive cells in the ipsilateral hemisphere were observed in IA, IV, and IC routes compared with PBS-treated rats. hUTC treatments did not reduce infarct volume when compared to the PBS groups. Our data indicate that hUTC administered via multiple routes provide therapeutic benefit after stroke. The enhancement of neurorestorative events in the host brain may contribute to the therapeutic benefits of hUTC in the treatment of stroke.

Death effector activation in the subventricular zone subsequent to perinatal hypoxia/ischemia.

Perinatal hypoxia/ischemia (H/I) is the leading cause of neurological injury resulting from birth complications and pre-maturity. Our studies have demonstrated that this injury depletes the subventricular zone (SVZ) of progenitors. In this study, we sought to reveal which cell death pathways are activated within these progenitors after H/I. We found that calpain activity is detected as early as 4 h of reperfusion and is sustained for 48 h, while caspase 3 activation does not occur until 8 h and peaks at 24 h post-insult. Activated calpains and caspase 3 co-localized within precursors situated in the lateral aspects of the SVZ (which coincides with progenitor cell death), whereas neither enzyme was activated in the medial SVZ (which harbors the neural stem cells that are resilient to this insult). These studies reveal targets for neuroprotective agents to protect precursors from cell death towards the goal of restoring normal brain development after H/I.

Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia.

Perinatal hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but approximately 50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions. We further show that production of new striatal neurons follows the expansion of NSPs. Increased proliferation within the NSP niche occurs at 2 d after perinatal H/I, and the proliferating cells express nestin. Of those stem-cell related genes that change, the membrane receptors Notch1, gp-130, and the epidermal growth factor receptor, as well as the downstream transcription factor Hes5, which stimulate NSP proliferation and regulate stem cellness are induced before NSP expansion. The mechanisms for the reactive expansion of the NSPs reported here reveal potential therapeutic targets that could be exploited to amplify this response, thus enabling endogenous precursors to restore a normal pattern of brain development after perinatal H/I.

Roles of the mammalian subventricular zone in cell replacement after brain injury.

The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated.

Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable.

Perinatal hypoxic-ischemic (H/I) brain injury remains a major cause of neurologic disability. Because we have previously demonstrated that this insult depletes cells from the subventricular zone (SVZ), the goal of the present investigation was to compare the relative vulnerability to H/I of neural stem cells versus progenitors. The dorsolateral SVZs of P6 rats were examined at 2 to 48 hours of recovery from H/I using hematoxylin and eosin, in situ end labeling (ISEL), terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), electron microscopy, and immunofluorescence. Pyknotic nuclei and ISEL cells were observed by 4 hours of recovery, peaked at 12 hours, and persisted for at least 48 hours. Many active-caspase-3 cells were observed at 12 hours and they comprised one third of the total TUNEL population. Electron microscopy revealed that hybrid cell deaths predominated at 12 hours of recovery. Importantly, few dying cells were observed in the medial SVZ, where putative stem cells reside, and no nestin medial SVZ cells showed caspase-3 activation. By contrast, active-caspase-3/PSA-NCAM progenitors were prominent in the lateral SVZ. These data demonstrate that early progenitors are vulnerable to H/I, whereas neural stem cells are resilient. The demise of these early progenitors may lead to the depletion of neuronal and late oligodendrocyte progenitors, contributing to cerebral dysgenesis after perinatal insults.

Roles of the mammalian subventricular zone in brain development.

There has been enormous progress in uncovering the contributions of the subventricular zone (SVZ) to the developing brain. Here, we review the roles of four anatomically defined embryologic divisions of the SVZ of the mammalian brain: the lateral ganglionic eminence (LGE), the medial ganglionic eminence (MGE), the caudal ganglionic eminence (CGE), and the fetal neocortical SVZ (SVZn), as well as the roles of the two major anatomically defined regions of the postnatal SVZ, the anterior SVZ (SVZa) and the dorsolateral SVZ (SVZdl). We describe the types of cells within each subdivision of the SVZ, the types of brain cells that they generate during embryonic, fetal, and perinatal development, and when known the mechanisms that regulate their differentiation. This review provides a critical analysis of the literature, from which current and future studies on the SVZ can be formulated and evaluated.