Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

Mineyeva, Olga A.; Bezriadnov, Dmitri V.; Kedrov, Alexander V.; Lazutkin, Alexander; Anokhin, Konstantin V.; Enikolopov, Grigori

doi:10.3389/fnins.2018.01013

Cited by 31 publications

(18 citation statements)

References 83 publications

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“…Another potent and long-term effect of irradiation involves impairing neurogenesis and cell proliferation (57,58). In line with these studies, we observe a signi cant decrease in doublecortin, a marker for neuronal precursor cells/neurogenesis, in the subgranular zone in the dentate gyrus of the hippocampus, a major site of neurogenesis in the mouse brain, following irradiation, which remains reduced following monocyte in ltration ( Fig.…”

Section: Lasting Effects Of Irradiation On Bbb Integrity Neurogenesisupporting

confidence: 84%

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

Preprint

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Background Microglia, the primary resident myeloid cells of brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e. monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1, and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain-region dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripheral derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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Section: Lasting Effects Of Irradiation On Bbb Integrity Neurogenesisupporting

confidence: 84%

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Another potent and long-term effect of irradiation involves impairing neurogenesis and cell proliferation [ 62 , 63 ]. In line with these studies, we observe a significant decrease in doublecortin, a marker for neuronal precursor cells/neurogenesis, in the subgranular zone of the dentate gyrus in the hippocampus, a major site of neurogenesis in the mouse brain, following irradiation, which remains reduced following monocyte infiltration (Fig.…”

Section: Resultsmentioning

confidence: 99%

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

J Neuroinflammation

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Background Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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“…In this study, the cumulative physical dose to organs at risk (OARs) was calculated adding the RT1 dose (reduced by 80% regarding the neuronal tissues capacity for recovery over the years (17)(18) to the RT2 prescribed dose. Cumulative OARs doses exceeded the QUANTEC dose constraints; however this was accepted considering the limited life expectancy of this group of patients.…”

Section: Discussionmentioning

confidence: 99%

Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma

et al. 2021

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BackgroundMany studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. MethodsThis is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent rst radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post rst failure OS (50% vs. 0%; p = 0.0010) was signi cantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was signi cantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). ConclusionRe-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.All radiation treatments were given at Garrahan Hospital, Buenos Aires, Argentina. Photon external beam therapy was used for all patients. All but four patients received CSI as part of the rst radiation course (RT1), followed by a boost to the entire posterior fossa. Standard risk (SR) patients received CSI 23.4Gy followed by posterior fossa boost 30.6Gy and high-risk (HR) patients received CSI 36Gy followed by posterior fossa boost 19.8Gy. Except for one, all of them received maintenance platinum based chemotherapy; SR as per ACNS0331 (N=2) and COG 9961 (regimen A=3, regimen B= 6); HR as per ACNS0332 (Regimen A=4, Regimen B=4). Four patients received upfront posterior fossa radiotherapy (54 Gy) due to the young age at diagnosis as per standard of care treatment administered between 2002 and 2020 at Hospital Garrahan, based on a modi ed POG-9934 strategy (15). Upon recurrence, most patients with brain solitary lesions were offered surgery followed by metronomic chemotherapy and a second course of irradiation (RT2), while those with multifocal disease received chemotherapy followed by radiotherapy. CSI was administered using standard beam's eye-view treatment planning techniques. Boost treatment and focal radiotherapy was administered using 3D-conformal radiation therapy methods. Hypofractionated stereotactic radiother...

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Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus

Cited by 31 publications

References 83 publications

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma

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