Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.

Uncovering a neural circuit controlling adult quiescent neural stem cell activation in the subventricular zone

The maintenance and differentiation of the adult neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. How neurogenesis in the SVZ is regulated by neural circuit activity remains poorly understood. Here we identified a novel neural circuit that regulates the state of lateral ventricular wall (LV) NSCs. Our results demonstrate that direct glutamatergic inputs from the frontal cortex, as well as local inhibitory interneurons, control the activity of subependymal cholinergic neurons. In vivo optogenetic and chemogenetic stimulation of defined neuronal populations within this circuit were sufficient to control LV NSC proliferation and SVZ neurogenesis. Moreover, acetylcholine (ACh), which activates M1 muscarinic ACh receptors, triggers the activation of quiescent NSCs. These findings shed light on neural activity-dependent regulation of postnatal and adult LV NSCs activation and SVZ neurogenesis.

Astrocyte and Oligodendrocyte Responses From the Subventricular Zone After Injury

Under normal conditions, neural stem cells (NSCs or B cells) in the adult subventricular zone (SVZ) give rise to amplifying neural progenitor cells (NPCs or C cells), which can produce neuroblasts (or A cells) that migrate to the olfactory bulb and differentiate into new neurons. However, following brain injury, these cells migrate toward the injury site where they differentiate into astrocytes and oligodendrocytes. In this review, we will focus on recent findings that chronicle how astrocytes and oligodendrocytes derived from SVZ-NSCs respond to different types of injury. We will also discuss molecular regulators of SVZ-NSC proliferation and their differentiation into astrocytes and oligodendrocytes. Overall, the goal of this review is to highlight how SVZ-NSCs respond to injury and to summarize the regulatory mechanisms that oversee their glial response. These molecular and cellular processes will provide critical insights needed to develop strategies to promote brain repair following injury using SVZ-NSCs.

Supratotal Resection of Periventricular Glioblastomas and Pathomorphological Rationale for Extensive Removal of Subventricular Zone

The aim of the research was to reveal the pathomorphological patterns of periventricular glioblastoma (PVG) dissemination and assess the rationale for extended surgical removal of subventricular zone (SVZ) as a step towards supratotal resection.A total of 54 patients (16 females and 38 males, mean age 48.9 ± 13.4 years, range 22–69) with PVG were prospectively included in the study. Standard preoperative evaluation included an MRI using 3D T1 with Gd-enhancement, T2, and T2-FLAIR series. The neuronavigation system was used to identify the SVZ and to remove of ventricular wall, additionally to image-guided total tumor resection. The pathomorphological assessment of PVG features with the description of the SVZ and changes in perifocal brain matter was performed by two pathologists.The median Karnofsky Performance Scale (KPS) score raised from 67.8 to 81.9 in the postoperative period. The overall median survival was 13.0 ± 2.7 months. The low postoperative KPS score (p = 0.05) and basal ganglia invasion (p = 0.008) significantly decreased survival rates.Microscopically, the typical multilayer structure of SVZ was disrupted. The invasive spread of tumor cells in thesubventricular space was identified. The ependymal layer had prominent dystrophic alterations of cells and destruction of intracellular connections. The hyperplastic reaction on neoplastic process was typical for adjacent ependyma.The pathomorphological identification of periventricular glioblastoma invasion in the subependymal space supports the supratotal tumor resection with removal of adjacent SVZ as a potential source for relapse.

IDH Wild-type Glioblastoma Presenting with Seizure: Clinical Specificity, and Oncologic and Surgical Outcomes.

Background Glioblastoma (GBM) is the most common and aggressive primary brain neoplasia in adults. Seizure is a common manifestation in GBM. Up to 25 to 60% of patients with GBM have seizures. We aim to summarize all the relevant clinical, surgical, radiologic, and molecular features of a cohort of patients suffering from GBM-related epilepsy and measure the outcome, to understand the possible existence of a clinical/phenotypical specificity of this subgroup of patients. Methods We retrospectively analyzed a cohort of 177 patients affected by isocitrate dehydrogenase wild-type (IDH-WT) GBM; 49 patients presented seizure at onset (SaO) and 128 were seizure free (SF). We investigated the relationship between seizures and other prognostic factors of GBMs. Results A statistically significant association between the location of the lesions in the parietal lobe and seizures was observed. The left side was more commonly affected. Interestingly, there was a statistical relationship between tumors involving the subventricular zone (SVZ) and SaO patients. The tumors were also smaller on average at diagnosis, and generalized SaOs were associated with longer overall survival. Conclusions The typical patient with IDH-WT GBM with SaO is a young (<55 year) male without a history of headache. The lesion is typically small to medium in size and located in the temporoparietal dominant lobe, with a high tendency to involve the SVZ.

NIMG-31. PROPOSED ORIGINS AND PATHWAYS OF DIFFUSE GLIOMAS REVEALED BY LESION COVARIANCE NETWORKS

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with high- and low-grade glioma, we identified – and replicated in an independent sample – three lesion covariance networks (LCNs), which reflect clusters of frequent glioma localization. These three LCNs overlapped with the anterior, posterior, and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal, and temporal cortices. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly coincided with multiple structural and functional connectivity networks, with LCN1 bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. These results build upon prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Cumulatively, our findings support a model wherein periventricular brain connectivity guides glioma development from the subventricular zone into distributed brain regions.

PATH-09. THE SEARCH FOR A NOVEL SUBTYPE OF GLIOBLASTOMA AND ITS CELL-OF-ORIGIN

Glioblastoma (GBM) has been computationally classified into three molecular subtypes (i.e., classical, proneural and mesenchymal). However, these subtypes lack strong biological and clinical implications. Therefore, our group has proposed to classify GBM according to its cell of origins. We have previously shown that different cell of origins give rise to biologically and transcriptionally distinct subtypes of GBM. We termed tumors that derived from subventricular zone (SVZ) neural stem cells as type 1 tumors and that from oligodendrocytic progenitor cells (OPC) as type 2 tumors. Based on murine lineage transcriptional profiles, we have also identified corresponding human GBM (40-50% of the TCGA GBM samples) tumors with conserved lineage properties. However, a majority of the TCGA GBM tumors remains unexplained by the cell-of-origin model. This study aims to search for other distinct GBM subtypes by addressing the tumorigenic potential of a putative stem progenitor population in the murine basilar pons. By using a recently reported Nestin transgenic mouse line (Nestin- C reERT2; e G FP-H2B; h D TR, or CGD in short), we have shown that conditionally deleting the commonly mutated glioma genes, Nf1 f/f ; Tp53 f/f and Pten f/+ (NPP), in pontine GFP+ cells, give rise to tumors that histologically resembles human GBM. Further transcriptomic analysis showed that a subset of these tumors highly express lineage markers of the differentiation-committed oligodendrocytic precursors (COP). We further probed the TCGA GBM database and identified 5% of the tumors to be enriched with our CGD pontine tumor-derived signature. In summary, our results showed that CGD-NPP cells can give rise to a previously uncharacterized tumor subtype with enrichment of COP lineage markers. Therefore, we propose COP as another cell of origin for GBM and that COP-derived tumor may contribute to a novel tumor subtype of the GBM classification.

Isolation and characterization of neural stem/progenitor cells in the subventricular zone of the naked mole-rat brain

Background The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear. Methods Neural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR. Results NMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs. Conclusions NMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.

3D Reconstitution of the Neural Stem Cell Niche: Connecting the Dots

Neural stem cells (NSCs) are important constituents of the nervous system, and they become constrained in two specific regions during adulthood: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. The SVZ niche is a limited-space zone where NSCs are situated and comprised of growth factors and extracellular matrix (ECM) components that shape the microenvironment of the niche. The interaction between ECM components and NSCs regulates the equilibrium between self-renewal and differentiation. To comprehend the niche physiology and how it controls NSC behavior, it is fundamental to develop in vitro models that resemble adequately the physiologic conditions present in the neural stem cell niche. These models can be developed from a variety of biomaterials, along with different biofabrication approaches that permit the organization of neural cells into tissue-like structures. This review intends to update the most recent information regarding the SVZ niche physiology and the diverse biofabrication approaches that have been used to develop suitable microenvironments ex vivo that mimic the NSC niche physiology.