Prospective Identification and Purification of Quiescent Adult Neural Stem Cells from Their In Vivo Niche

Codega, Paolo; Silva-Vargas, Violeta; Paul, Alex; Maldonado-Soto, Angel R.; DeLeo, Annina M.; Pastrana, Érika; Doetsch, Fiona

doi:10.1016/j.neuron.2014.02.039

Cited by 569 publications

(862 citation statements)

References 85 publications

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“…This hypothesis is consistent with the previously described alterations in the cell cycle of aged NSPCs (Apostolopoulou et al., 2017; Daynac et al., 2014, 2016; Stoll et al., 2011). Dbx2 is part of a cohort of transcription factor genes that are enriched in quiescent NSPCs of the SGZ and SVZ and are downregulated in NSPCs actively engaged in cell proliferation and neurogenesis (Codega et al., 2014; Shin et al., 2015), thus suggesting that Dbx2 may negatively regulate NSPC proliferation in both adult neurogenic niches. Elevated Dbx2 expression in adult NSPCs also phenocopied several of the molecular effects of aging, including the altered expression of key genes such as Sox2 and p21 that are associated with proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

et al. 2018

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SummaryAdult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age‐associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ‐derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age‐dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age‐related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age‐associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age‐related neurogenic decline.

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Section: Discussionmentioning

confidence: 99%

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

et al. 2018

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“…Table 2), demonstrating similarities in metabolic programs between reactive astrocytes and NSCs different from the ones of normal parenchymal astrocytes. This is particularly intriguing, as metabolic pathways have been shown to be key in regulating fate decisions and changes (see, e.g., Maryanovich and Gross, 2013) and specific aspects of the lipid metabolism have been identified as a key pathway regulating adult NSC activity (Bracko et al, 2012; Codega et al, 2014; Knobloch et al, 2013). Thus, the metabolic signatures shared between SEZ NSCs and reactive astrocytes are likely involved in regulating the transition of astrocytes to a more plastic progenitor/NSC‐like phenotype after injury.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

116

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Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins—Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere‐forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes. GLIA 2015;63:2340–2361

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“…Stem cells in the adult V-SVZ exist in quiescent and activated (dividing) states [23], and give rise to neurons, as well as to glia. Both the levels of adult neurogenesis, and the destination of newly generated neurons exhibit species-specific differences [17,104].…”

Section: Adultmentioning

confidence: 99%

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

et al. 2018

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The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

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Prospective Identification and Purification of Quiescent Adult Neural Stem Cells from Their In Vivo Niche

Cited by 569 publications

References 85 publications

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

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