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The aged brain: genesis and fate of residual progenitor cells in the subventricular zone.

Capilla-Gonzalez V, Herranz-Pérez V, García-Verdugo JM - Front Cell Neurosci (2015)

Bottom Line: This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain.It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised.Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Comparative Neurobiology, Department of Cell Biology, Instituto Cavanilles de Biodiversidad y Biología Evolutiva, University of Valencia, CIBERNED Valencia, Spain ; Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain.

ABSTRACT
Neural stem cells (NSCs) persist in the adult mammalian brain through life. The subventricular zone (SVZ) is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the SVZ suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence.

No MeSH data available.


Related in: MedlinePlus

Age-related changes in the ultrastructure of the neurogenic niches. (A,A′) Astrocytes accumulate dense bodies (box) in their cytoplasm during aging. Scale bar: 2 micra. (B,B′) Detail of intermediate filaments (arrows) in astrocytic cells. Note that they are more abundant in aged cells. Scale bar: 500 nm. (C,C′) Detail of lipid droplets in ependymal cells, displaying a larger size during aging. Scale bar: 5 micra. (D,D′) Ependymal cells are flattened in the aged brain, resulting in large gaps between ciliary tufts (arrows). Scale bar: 2 micra. (E) Under scanning electron microscopy, whole-mount preparation of the lateral ventricle shows a deep network of axons (arrows) in the aged brain. Scale bar: 5 micra. (F) DAPI (4′,6-diamidino-2-phenylindole) fluorescent staining shows a remarkable RMS (arrows) from the lateral ventricle to the OB in the young brain. Scale bar: 1 mm. (G) Conversely, the RMS is not evident in the aged brain. Scale bar: 1 mm. b, astrocyte; e, ependymal cell; Cb, cerebellum; Ctx, cerebral cortex; Lp, lipid droplets; Lv, lateral ventricle; OB, olfactory bulb. Images (F,G) have been adapted with permission from Capilla-Gonzalez et al. (2013).
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Figure 2: Age-related changes in the ultrastructure of the neurogenic niches. (A,A′) Astrocytes accumulate dense bodies (box) in their cytoplasm during aging. Scale bar: 2 micra. (B,B′) Detail of intermediate filaments (arrows) in astrocytic cells. Note that they are more abundant in aged cells. Scale bar: 500 nm. (C,C′) Detail of lipid droplets in ependymal cells, displaying a larger size during aging. Scale bar: 5 micra. (D,D′) Ependymal cells are flattened in the aged brain, resulting in large gaps between ciliary tufts (arrows). Scale bar: 2 micra. (E) Under scanning electron microscopy, whole-mount preparation of the lateral ventricle shows a deep network of axons (arrows) in the aged brain. Scale bar: 5 micra. (F) DAPI (4′,6-diamidino-2-phenylindole) fluorescent staining shows a remarkable RMS (arrows) from the lateral ventricle to the OB in the young brain. Scale bar: 1 mm. (G) Conversely, the RMS is not evident in the aged brain. Scale bar: 1 mm. b, astrocyte; e, ependymal cell; Cb, cerebellum; Ctx, cerebral cortex; Lp, lipid droplets; Lv, lateral ventricle; OB, olfactory bulb. Images (F,G) have been adapted with permission from Capilla-Gonzalez et al. (2013).

Mentions: During aging, remaining ependymal and astrocytic cells accumulate dense bodies and intermediate filaments in their cytoplasm (Figures 2A,A′,B,B′), resembling reactive cells (Bouab et al., 2011; Capilla-Gonzalez et al., 2014a). The acquisition of a reactive phenotype in astrocytes may imply a reduction in their stemness. In fact, most of the astrocytic cells found in the aged SVZ were identified as non-neurogenic astrocytes, since they showed a lack of ventricular contact (Capilla-Gonzalez et al., 2014a). Thus, the major characteristic of aging is the reduction in proliferation that occurs in the germinal niche. Furthermore, ependymal cells in the aged SVZ present larger lipid droplets than those from young mice (Figure 2C,C′), as well as they are more flattened, which results in more dispersed cilia tufts (Luo et al., 2008; Bouab et al., 2011; Capilla-Gonzalez et al., 2014a) (Figure 2D,D′). Reports have indicated that the network of axons presented in the ventricle surface can influence the morphology of the ependymal cells. As consequence, changes in this axonal network during aging may result in the flattening of the ependymal layer. Although it has been found that the network of axons presented in the ventricle surface increases with age (Lorez and Richards, 1982; Capilla-Gonzalez et al., 2014a; Tong et al., 2014) (Figure 2E), its role in modifying ependymal cell morphology needs to be clarified. Ependymal cilia are required for normal cerebrospinal fluid flow that allows neuroblast migration based on guidance cues (Sawamoto et al., 2006; Mirzadeh et al., 2010; Young et al., 2012). Thus, the age-related changes in ependymal cilia could contribute to the reduced migration observed in old mice. In line with this idea, a similar cilia organization was observed in mice exposed to the environmental toxic N-ethyl-N-nitrosourea (ENU). Under scanning electron microscopy, the ventricle surface of these animals displayed a disorganized cilia orientation and frequent patches devoid of cilia following ENU-exposure. This ependymal ciliary dysfunction was associated with declined incorporation of SVZ-derived neuroblasts to the OB and a subsequent impairment in odor discrimination (Capilla-Gonzalez et al., 2010, 2012). Another structure that plays an important role in the adult SVZ are fractones, which are composed of ubiquitous extracellular matrix components, including heparin sulfate proteoglycans such as perlecan and agrin. Fractones can regulate neurogenesis by capturing different growth factors (Douet et al., 2012, 2013). It has been reported that aging gradually affects the number, size, and composition of these structures suggesting that, through their interaction with NSCs, fractons could be related to the loss of neurogenesis during aging (Kerever et al., 2015). According to this, changes in fractone ultrastructure have been described in an experimental obstruction model of hydrocephalus in mice, which showed decreased NSCs proliferation in the SVZ (Campos-Ordoñez et al., 2014). Future studies will provide a more comprehensive understanding on the function of fractones in the neurogenic niche. The direct consequence of aging impact on the SVZ neurogenic niche is the progressive reduction of migrating neuroblasts toward the OB (Figures 2F,G). Indeed, several studies reported how RMS is notably reduced in elderly rodent (Bouab et al., 2011; Capilla-Gonzalez et al., 2013), resulting in a severe disruption of the SVZ-RMS axis.


The aged brain: genesis and fate of residual progenitor cells in the subventricular zone.

Capilla-Gonzalez V, Herranz-Pérez V, García-Verdugo JM - Front Cell Neurosci (2015)

Age-related changes in the ultrastructure of the neurogenic niches. (A,A′) Astrocytes accumulate dense bodies (box) in their cytoplasm during aging. Scale bar: 2 micra. (B,B′) Detail of intermediate filaments (arrows) in astrocytic cells. Note that they are more abundant in aged cells. Scale bar: 500 nm. (C,C′) Detail of lipid droplets in ependymal cells, displaying a larger size during aging. Scale bar: 5 micra. (D,D′) Ependymal cells are flattened in the aged brain, resulting in large gaps between ciliary tufts (arrows). Scale bar: 2 micra. (E) Under scanning electron microscopy, whole-mount preparation of the lateral ventricle shows a deep network of axons (arrows) in the aged brain. Scale bar: 5 micra. (F) DAPI (4′,6-diamidino-2-phenylindole) fluorescent staining shows a remarkable RMS (arrows) from the lateral ventricle to the OB in the young brain. Scale bar: 1 mm. (G) Conversely, the RMS is not evident in the aged brain. Scale bar: 1 mm. b, astrocyte; e, ependymal cell; Cb, cerebellum; Ctx, cerebral cortex; Lp, lipid droplets; Lv, lateral ventricle; OB, olfactory bulb. Images (F,G) have been adapted with permission from Capilla-Gonzalez et al. (2013).
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Related In: Results  -  Collection

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Show All Figures
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Figure 2: Age-related changes in the ultrastructure of the neurogenic niches. (A,A′) Astrocytes accumulate dense bodies (box) in their cytoplasm during aging. Scale bar: 2 micra. (B,B′) Detail of intermediate filaments (arrows) in astrocytic cells. Note that they are more abundant in aged cells. Scale bar: 500 nm. (C,C′) Detail of lipid droplets in ependymal cells, displaying a larger size during aging. Scale bar: 5 micra. (D,D′) Ependymal cells are flattened in the aged brain, resulting in large gaps between ciliary tufts (arrows). Scale bar: 2 micra. (E) Under scanning electron microscopy, whole-mount preparation of the lateral ventricle shows a deep network of axons (arrows) in the aged brain. Scale bar: 5 micra. (F) DAPI (4′,6-diamidino-2-phenylindole) fluorescent staining shows a remarkable RMS (arrows) from the lateral ventricle to the OB in the young brain. Scale bar: 1 mm. (G) Conversely, the RMS is not evident in the aged brain. Scale bar: 1 mm. b, astrocyte; e, ependymal cell; Cb, cerebellum; Ctx, cerebral cortex; Lp, lipid droplets; Lv, lateral ventricle; OB, olfactory bulb. Images (F,G) have been adapted with permission from Capilla-Gonzalez et al. (2013).
Mentions: During aging, remaining ependymal and astrocytic cells accumulate dense bodies and intermediate filaments in their cytoplasm (Figures 2A,A′,B,B′), resembling reactive cells (Bouab et al., 2011; Capilla-Gonzalez et al., 2014a). The acquisition of a reactive phenotype in astrocytes may imply a reduction in their stemness. In fact, most of the astrocytic cells found in the aged SVZ were identified as non-neurogenic astrocytes, since they showed a lack of ventricular contact (Capilla-Gonzalez et al., 2014a). Thus, the major characteristic of aging is the reduction in proliferation that occurs in the germinal niche. Furthermore, ependymal cells in the aged SVZ present larger lipid droplets than those from young mice (Figure 2C,C′), as well as they are more flattened, which results in more dispersed cilia tufts (Luo et al., 2008; Bouab et al., 2011; Capilla-Gonzalez et al., 2014a) (Figure 2D,D′). Reports have indicated that the network of axons presented in the ventricle surface can influence the morphology of the ependymal cells. As consequence, changes in this axonal network during aging may result in the flattening of the ependymal layer. Although it has been found that the network of axons presented in the ventricle surface increases with age (Lorez and Richards, 1982; Capilla-Gonzalez et al., 2014a; Tong et al., 2014) (Figure 2E), its role in modifying ependymal cell morphology needs to be clarified. Ependymal cilia are required for normal cerebrospinal fluid flow that allows neuroblast migration based on guidance cues (Sawamoto et al., 2006; Mirzadeh et al., 2010; Young et al., 2012). Thus, the age-related changes in ependymal cilia could contribute to the reduced migration observed in old mice. In line with this idea, a similar cilia organization was observed in mice exposed to the environmental toxic N-ethyl-N-nitrosourea (ENU). Under scanning electron microscopy, the ventricle surface of these animals displayed a disorganized cilia orientation and frequent patches devoid of cilia following ENU-exposure. This ependymal ciliary dysfunction was associated with declined incorporation of SVZ-derived neuroblasts to the OB and a subsequent impairment in odor discrimination (Capilla-Gonzalez et al., 2010, 2012). Another structure that plays an important role in the adult SVZ are fractones, which are composed of ubiquitous extracellular matrix components, including heparin sulfate proteoglycans such as perlecan and agrin. Fractones can regulate neurogenesis by capturing different growth factors (Douet et al., 2012, 2013). It has been reported that aging gradually affects the number, size, and composition of these structures suggesting that, through their interaction with NSCs, fractons could be related to the loss of neurogenesis during aging (Kerever et al., 2015). According to this, changes in fractone ultrastructure have been described in an experimental obstruction model of hydrocephalus in mice, which showed decreased NSCs proliferation in the SVZ (Campos-Ordoñez et al., 2014). Future studies will provide a more comprehensive understanding on the function of fractones in the neurogenic niche. The direct consequence of aging impact on the SVZ neurogenic niche is the progressive reduction of migrating neuroblasts toward the OB (Figures 2F,G). Indeed, several studies reported how RMS is notably reduced in elderly rodent (Bouab et al., 2011; Capilla-Gonzalez et al., 2013), resulting in a severe disruption of the SVZ-RMS axis.

Bottom Line: This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain.It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised.Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Comparative Neurobiology, Department of Cell Biology, Instituto Cavanilles de Biodiversidad y Biología Evolutiva, University of Valencia, CIBERNED Valencia, Spain ; Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine Seville, Spain.

ABSTRACT
Neural stem cells (NSCs) persist in the adult mammalian brain through life. The subventricular zone (SVZ) is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the SVZ suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence.

No MeSH data available.


Related in: MedlinePlus