Altered Fate of Subventricular Zone Progenitor Cells and Reduced Neurogenesis following Neonatal Stroke

Abstract

Objective: To investigate the effects of neonatal stroke on progenitor cells lining the lateral ventricles. Methods: Intraventricular injection of replication-incompetent green fluorescent protein (GFP)-expressing lentivirus was performed in postnatal day 1 (P1) rats to specifically label radial glia/type B neural stem cells and ependymal cells of the lateral ventricle. A subset of animals was exposed to transient middle cerebral artery occlusion (MCAO) at P7, with mild or moderate injury confirmed by diffusion-weighted MRI and histology. Newborn cells were identified by GFP expression, location and expression of cell type-specific markers in the striatum, cortex and olfactory bulb using confocal microscopy and systematic random sampling. Results: Three weeks lentiviral GFP transduction of cells in the lateral ventricle, abundant GFP-expressing neurons and glia were identified in the rostral migratory stream, olfactory bulb and striatum as expected from labeling the subventricular zone (SVZ) type B neural stem cell lineage. Two weeks following mild or severe focal stroke at P7, no GFP-expressing neurons were detected in striatum or cortex although some single-labeled doublecortin+ immature neurons were detected in the penumbra. The densities of GFP+/ glial fibrillary acidic protein (GFAP)+ astrocytes and GFP+/O4+ oligodendrocytes were reduced in the striatum following MCAO (4.8 ± 1.02 vs. 2.5 ± 0.4 cells/high-power field, HPF; p = 0.005; 2.8± 1 vs. 0.5 ± 0.2 cells/HPF, p = 0.008). Furthermore, there was a reduction of GFP+ cells in the olfactory bulb following MCAO (58.8 ± 14.9 vs. 19.6 ± 5.4 cells/HPF, p = 0.025). Finally, there was an increased percentage of GFP+/GFAP+ cells (70 vs. 50%), with a decreased proportion of GFP+/O4+ cells (14 vs. 30%) in injured animals. Conclusion: Neurogenesis originating from cells of the lateral ventricle, including SVZ type B cells, is significantly reduced following neonatal stroke. Furthermore, neonatal stroke disrupts gliogenesis in the striatum, decreasing overall numbers of new glia and shifting the population towards astrocytes.

Intrauterine Growth Restriction: Effects on Neural Precursor Cell Proliferation and Angiogenesis in the Foetal Subventricular Zone

“…Several studies have highlighted the capacity of neural progenitor cells within the neonatal SVZ to respond to injury as a result of hypoxia or hypoxia-ischaemia and have reported both an increase [10,11,12,13,14] and a decrease [15,16,17] in proliferation. Relatively little, however, is known concerning the foetus.…”

“…A possible site of such a response is the subventricular zone (SVZ) - the neurogenic zone in the forebrain from which neurons and neuroglia are generated in later stages of foetal development [9]. This area has been shown to respond to hypoxic insults, albeit in the neonate, with increased cell proliferation [10,11,12,13,14], although there have also been reports of decreased proliferation [15,16,17]. Specifically, the aims of this study were as follows: (1) to determine the ongoing effects of CPI on cell proliferation in the foetal SVZ; (2) to characterise the phenotype of the proliferating cells; (3) to identify alterations to specific cellular components (astrocytes and microglia) of the compromised microenvironment, and (4) to identify any association between the cerebral microvasculature and cell proliferation in the compromised SVZ.…”

Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

“…Finally, it is important to mention that levels of neurogenesis are permanently affected also by other ELS not necessarily related to the mother-infant interaction alone. For example, ELS inflammation (Jakubs et al 2008;Musaelyan et al 2014), radiation therapy (Fukuda et al 2005;Naylor et al 2008;Hoffman and Yock 2009), anesthesia (Zhu et al 2010), stroke (Spadafora et al 2010), infection (Bland et al 2010), and ethanol exposure (Singh et al 2009) induce long-lasting effects on neurogenesis associated with late-onset cognitive impairment. Thus, the studies described have shown that EL experiences during both pre-and postnatal development can bidirectionally alter hippocampal neuronal plasticity and synaptic integrity.…”

Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus

“…While hypoxic injury may stimulate neurogenesis, it may also inhibit neural regeneration by eliminating NSPCs or by reducing rates of proliferation. Studies of the SVZ in neonatal rodents show that HI causes loss of NSPCs via mechanisms of apoptotic cell death [16,17,18], suggesting that neuroprotection for NSPCs could be an important means of promoting regeneration and repair. …”