scholarly journals Activation of a neural stem cell transcriptional program in parenchymal astrocytes

2020 ◽  
Author(s):  
Jens P. Magnusson ◽  
Margherita Zamboni ◽  
Giuseppe Santopolo ◽  
Jeff E. Mold ◽  
Mauricio Barrientos-Somarribas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Brain Regions ◽  
Adult Brain ◽  
Targeted Interventions ◽  
Physiological Conditions ◽  
Neuronal Lineage ◽  
Epidermal Growth

AbstractNeural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells and progressed through a nearly identical neurogenic program. Surprisingly, in the non- neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, the cortical astrocytes, and many striatal ones, stalled before entering transit- amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

scholarly journals Activation of a neural stem cell transcriptional program in parenchymal astrocytes

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jens P Magnusson ◽  
Margherita Zamboni ◽  
Giuseppe Santopolo ◽  
Jeff E Mold ◽  
Mauricio Barrientos-Somarribas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Brain Regions ◽  
Transcriptional Program ◽  
Targeted Interventions ◽  
Physiological Conditions ◽  
Neuronal Lineage ◽  
Epidermal Growth

Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells, progressing through a near-identical neurogenic program. Surprisingly, in the non-neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, these cortical astrocytes, and many striatal ones, stalled before entering transit-amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

scholarly journals Basal neural stem cells in the subventricular zone drive postnatal neurogenesis with apical stem cells acting as proliferation gate-keepers

2020 ◽  
Author(s):  
Katja Baur ◽  
Yomn Abdullah ◽  
Claudia Mandl ◽  
Gabriele Hölzl-Wenig ◽  
Yan Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Lateral Inhibition ◽  
Subventricular Zone ◽  
Primary Cilia ◽  
List Type ◽  
Inhibition Of Proliferation ◽  
Neural Lineage ◽  
Notch Activation

ABSTRACTNeural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ) contribute to olfaction by being the origin of most adult-born olfactory bulb (OB) interneurons. The current consensus maintains that adult NSCs are radial glialike progenitors apically contacting the lateral ventricle and generating intermediate progenitors migrating at the basal V-SVZ. Whether basal NSCs are present in the V-SVZ is unknown. We here used genetic tagging of NSCs in vivo and additional labelling approaches to reveal that basal NSCs lacking apical attachment represent the largest NSC type in the postnatal V-SVZ from birth onwards. Despite dividing faster than their apical counterpart, basal NSCs still undergo long-term self-renewal and quiescence. Unlike apical NSCs, they are largely devoid of primary cilia and Prominin-1, Nestin and glial fibrillary acidic protein (GFAP) immunoreactivity. Six weeks after viral tagging of apical cells, few descendant cells were detected in the basal V-SVZ, including Sox9+ progenitors and GFAP+ astrocytes, and very rare new neurons in the OB, indicating that adult-born OB neurons originate from basal and not apical NSCs. Consistent with this, we found that pregnancy, a physiological modulator of adult OB neurogenesis, selectively increases the number of basal but not apical NSCs. Lastly, we find that apical NSCs display the highest levels of Notch activation in the neural lineage, and that selective apical downregulation of Notch-signaling effector Hes1 decreases Notch activation while increasing proliferation across the V-SVZ. Thus, apical NSCs act essentially as neurogenesis gatekeepers by modulating Notch-mediated lateral inhibition of proliferation in the adult V-SVZ.Graphical AbstractHighlightsBasal NSCs are the most abundant stem cell type in the adult V-SVZ from birth onwards.Apical and basal NSCs display distinct characteristics and cell cycle progression dynamics.Apical NSCs are not the main source of newly generated adult OB interneurons.Apical NSCs regulate intermediate progenitor proliferation by orchestrating Notch-mediated lateral inhibition.

Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury

2014 ◽  
Vol 37 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Matthew T. Goodus ◽  
Alanna M. Guzman ◽  
Frances Calderon ◽  
Yuhui Jiang ◽  
Steven W. Levison
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Flow Cytometry ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Proliferative Response ◽  
Fold Increase ◽  
Adult Brain ◽  
Neural Precursors

Pediatric traumatic brain injury is a significant problem that affects many children each year. Progress is being made in developing neuroprotective strategies to combat these injuries. However, investigators are a long way from therapies to fully preserve injured neurons and glia. To restore neurological function, regenerative strategies will be required. Given the importance of stem cells in repairing damaged tissues and the known persistence of neural precursors in the subventricular zone (SVZ), we evaluated regenerative responses of the SVZ to a focal brain lesion. As tissues repair more slowly with aging, injury responses of male Sprague Dawley rats at 6, 11, 17, and 60 days of age and C57Bl/6 mice at 14 days of age were compared. In the injured immature animals, cell proliferation in the dorsolateral SVZ more than doubled by 48 h. By contrast, the proliferative response was almost undetectable in the adult brain. Three approaches were used to assess the relative numbers of bona fide neural stem cells, as follows: the neurosphere assay (on rats injured at postnatal day 11, P11), flow cytometry using a novel 4-marker panel (on mice injured at P14) and staining for stem/progenitor cell markers in the niche (on rats injured at P17). Precursors from the injured immature SVZ formed almost twice as many spheres as precursors from uninjured age-matched brains. Furthermore, spheres formed from the injured brain were larger, indicating that the neural precursors that formed these spheres divided more rapidly. Flow cytometry revealed a 2-fold increase in the percentage of stem cells, a 4-fold increase in multipotential progenitor-3 cells and a 2.5-fold increase in glial-restricted progenitor-2/multipotential-3 cells. Analogously, there was a 2-fold increase in the mitotic index of nestin+/Mash1- immunoreactive cells within the immediately subependymal region. As the early postnatal SVZ is predominantly generating glial cells, an expansion of precursors might not necessarily lead to the production of many new neurons. On the contrary, many BrdU+/doublecortin+ cells were observed streaming out of the SVZ into the neocortex 2 weeks after injuries to P11 rats. However, very few new mature neurons were seen adjacent to the lesion 28 days after injury. Altogether, these data indicate that immature SVZ cells mount a more robust proliferative response to a focal brain injury than adult cells, which includes an expansion of stem cells, primitive progenitors and neuroblasts. Nonetheless, this regenerative response does not result in significant neuronal replacement, indicating that new strategies need to be implemented to retain the regenerated neurons and glia that are being produced.

scholarly journals Activated Neural Stem Cells Contribute to Stroke-Induced Neurogenesis and Neuroblast Migration toward the Infarct Boundary in Adult Rats

2004 ◽  
Vol 24 (4) ◽  
pp. 441-448 ◽  
Author(s):  
Ruilan Zhang ◽  
Zhenggang Zhang ◽  
Lei Wang ◽  
Ying Wang ◽  
Anton Gousev ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Proliferating Cells ◽  
Adult Rats ◽  
Antimitotic Agent ◽  
Neuroblast Migration ◽  
Ipsilateral Striatum

Stroke increases neurogenesis. The authors investigated whether neural stem cells or progenitor cells in the adult subventricular zone (SVZ) of rats contribute to stroke-induced increase in neurogenesis. After induction of stroke in rats, the numbers of cells immunoreactive to doublecortin, a marker for immature neurons, increased in the ipsilateral SVZ and striatum. Infusion of an antimitotic agent (cytosine-β-D-arabiofuranoside, Ara-C) onto the ipsilateral cortex eliminated more than 98% of actively proliferating cells in the SVZ and doublecortin-positive cells in the ipsilateral striatum. However, doublecortin-positive cells rapidly replenished after antimitotic agent depletion of actively proliferating cells. Depleting the numbers of actively proliferating cells in vivo had no effect on the numbers of neurospheres formed in vitro, yet the numbers of neurospheres derived from stroke rats significantly ( P < 0.05) increased. Neurospheres derived from stroke rats self-renewed and differentiated into neurons and glia. In addition, doublecortin-positive cells generated in the SVZ migrated in a chainlike structure toward ischemic striatum. These findings indicate that in the adult stroke brain, increases in recruitment of neural stem cells contribute to stroke-induced neurogenesis, and that newly generated neurons migrate from the SVZ to the ischemic striatum.

Pax6 regulates the epidermal growth factor-responsive neural stem cells of the subventricular zone

Neuroreport ◽  
2011 ◽  
Vol 22 (9) ◽  
pp. 448-452 ◽  
Author(s):  
Haitao Jia ◽  
Hong Tao ◽  
Ruopeng Feng ◽  
Meiyu Li ◽  
Jie Bai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Epidermal Growth

scholarly journals Mobilization of Neural Stem Cells and Generation of New Neurons in 6-OHDA–lesioned Rats by Intracerebroventricular Infusion of Liver Growth Factor

2009 ◽  
Vol 57 (5) ◽  
pp. 491-502 ◽  
Author(s):  
Rafael Gonzalo-Gobernado ◽  
Diana Reimers ◽  
Antonio S. Herranz ◽  
Juan José Díaz-Gil ◽  
Cristina Osuna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Adult Brain ◽  
Proliferating Cells ◽  
Liver Growth ◽  
Neuronal Nuclei ◽  
Intracerebroventricular Infusion ◽  
6 Hydroxydopamine

Neural stem cells with self-renewal and multilineage potential persist in the subventricular zone of the adult mammalian forebrain. These cells remain relatively quiescent but, under certain conditions, can be stimulated, giving rise to new neurons. Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and is useful for neuroregenerative therapies. The aim of this study was to investigate the potential neurogenic activity of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Proliferation was significantly increased in the subventricular zone and denervated striatum of rats receiving ICV LGF infusions, and 25% of the proliferating cells were doublecortin-positive neurons. Doublecortin-positive cells with the morphology of migrating neuroblasts were also observed in the dorsal and ventral regions of the striatum of LGF-infused animals. Moreover, some newly generated cells were neuronal nuclei-positive mature neurons. LGF also stimulated microglia and induced astrogliosis, both phenomena associated with generation and migration of new neurons in the adult brain. In summary, our study shows that LGF stimulates neurogenesis when applied intraventricularly in 6-hydroxydopamine–lesioned rats. Considering that this factor also promotes neuronal migration into damaged tissue, we propose LGF as a novel factor useful for neuronal replacement in neurodegenerative diseases. (J Histochem Cytochem 57:491–502, 2009)

scholarly journals On the Genesis of Neuroblastoma and Glioma

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Jan de Weille
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Clinical Data ◽  
Subventricular Zone ◽  
Adult Brain ◽  
Replication Errors ◽  
Genomic Damage ◽  
Pros And Cons

As the emergence of cancer is most frequent in proliferating tissues, replication errors are considered to be at the base of this disease. This review concentrates mainly on two neural cancers, neuroblastoma and glioma, with completely different backgrounds that are well documented with respect to their ontogeny. Although clinical data on other cancers of the nervous system are available, usually little can be said about their origins. Neuroblastoma is initiated in the embryo at a moment when the nervous system (NS) is in full expansion and occasionally genomic damage can lead to neoplasia. Glioma, to the contrary, occurs in the adult brain supposed to be mostly in a postmitotic state. According to current consensus, neural stem cells located in the subventricular zone (SVZ) in the adult are thought to accumulate enough genomic mutations to diverge on a carcinogenic course leading to diverse forms of glioma. After weighing the pros and cons of this current hypothesis in this review, it will be argued that this may be improbable, yielding to the original old concept of glial origin of glioma.

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