The hippocampal neurovascular niche during normal development and after irradiation to the juvenile mouse brain

Boström, Martina; Erkenstam, Nina Hellström; Kaluza, David; Jakobsson, Lars; Kalm, Marie; Blomgren, Klas

doi:10.3109/09553002.2014.931612

Cited by 19 publications

(10 citation statements)

References 58 publications

(69 reference statements)

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“…Our data show that a dose of radiation as low as 4 Gy is sufficient to suppress cell proliferation to approximately 6% of control levels, 24 hours after exposure. This is consistent with evidence that the majority of apoptosis among progenitor cells in the SGZ occurs within 24 hours after radiation [ 54 ] and other reports of a long-lasting decrease in proliferation or neurogenesis in the rodent hippocampus following cranial radiation in early development [ 55 – 58 ]. Disruption of hippocampal neurogenesis during development, especially if persistent, may well contribute to the decrease in brain size that we have observed [ 59 , 60 ] ( Figure 7(b) ) as well as late cognitive sequelae of childhood CRT [ 43 , 61 , 62 ].…”

Section: Discussionsupporting

confidence: 92%

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

et al. 2016

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Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT.

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Section: Discussionsupporting

confidence: 92%

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

et al. 2016

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“…Studies have also identified endothelial cells as a critical component of the neural stem cell niche and shown that they are involved in the regulation of stem and progenitor cell proliferation and differentiation4142. Irradiation disrupts the neurovascular niche both in the adult and juvenile developing brain4143, and might influence stem and progenitor cell proliferation and differentiation, as well as injury and repair. In the juvenile rat brain, we found that BBB disruption after irradiation varies among brain regions and that the cerebellum is the most sensitive region to irradiation in this respect.…”

Section: Discussionmentioning

confidence: 99%

Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum

Zhou

Boström

et al. 2017

Sci Rep

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Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient’s quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.

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“…With one exception (Boström et al, 2014), previous reconstructions had not explicitly included pericytes (Palmer et al, 2000). Nestin-GFP + hippocampal precursor cells have vascular endfeet ( Fig.…”

Section: The Hippocampal Niche In Vivomentioning

confidence: 99%

A co-culture model of the hippocampal neurogenic niche reveals differential effects of astrocytes, endothelial cells and pericytes on proliferation and differentiation of adult murine precursor cells

2015

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The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.

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The hippocampal neurovascular niche during normal development and after irradiation to the juvenile mouse brain

Abstract: The hippocampal neurovascular niche in the young, growing brain is transiently disrupted by irradiation. It remains to be elucidated what role these transient changes play in the apparently permanent ablation of hippocampal neurogenesis previously demonstrated in the same model.

Cited by 19 publications

References 58 publications

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum

A co-culture model of the hippocampal neurogenic niche reveals differential effects of astrocytes, endothelial cells and pericytes on proliferation and differentiation of adult murine precursor cells

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