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 27 publications

(12 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

“…4(C). This suggests a potential differentiated phenotype [21] and provided a possible explanation for the radio-sensitisation effects of INDY and L41 [23].…”

Section: Dyrk1a Inhibitors Sensitized the Ren Vm Spheroids To The Radiationmentioning

confidence: 74%

ReN VM spheroids in matrix: A neural progenitor three-dimensional in vitro model reveals DYRK1A inhibitors as potential regulators of radio-sensitivity

Wan

Hill

et al. 2020

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Introduction: Pre-clinical testing of small molecules for therapeutic development across many pathologies relies on the use of in-vitro and in-vivo models. When designed and implemented well, these models serve to predict the clinical outcome as well as the toxicity of the evaluated therapies. The two-dimensional (2D) reductionist approach where cells are incubated in a mono-layer on hard plastic microtiter plates is relatively inexpensive but not physiologically relevant. In contrast, well developed and applied three dimensional (3D) in vitro models could be employed to bridge the gap between 2D in vitro primary screening and expensive in vivo rodent models by incorporating key features of the tissue microenvironment to explore differentiation, cortical development, cancers and various neuronal dysfunctions. These features include an extracellular matrix, co-culture, tension and perfusion and could replace several hundred rodents in the drug screening validation cascade. Methods: Human neural progenitor cells from middle brain (ReN VM, Merck Millipore, UK) were expanded as instructed by the supplier (Merck Millipore, UK), and then seeded in 96-well low-attachment plates (Corning, UK) to form multicellular spheroids followed by adding a Matrigel layer to mimic extracellular matrix around neural stem cell niche. ReN VM cells were then differentiated via EGF and bFGF deprivation for 7 days and were imaged at day 7. Radiotherapy was mimicked via gamma-radiation at 2Gy in the absence and presence of selected DYRK1A inhibitors Harmine, INDY and Leucettine 41 (L41). Cell viability was measured by AlamarBlue assay. Immunofluorescence staining was used to assess cell pluripotency marker SOX2 and differentiation marker GFAP. Results: After 7 days of differentiation, neuron early differentiation marker (GFAP, red) started to be expressed among the cells expressing neural stem cell marker SOX2 (green). Radiation treatment caused significant morphology change including the reduced viability of the spheroids. These spheroids also revealed sensitizing potential of DYRK1A inhibitors tested in this study, including Harmine, INDY and L41. Discussion & conclusions: Combined with the benefit of greatly reducing the issues associated with in vivo rodent models, including reducing numbers of animals used in a drug screening cascade, cost, ethics, and potential animal welfare burden, we feel the well-developed and applied 3D neural spheroid model presented in this study will provide a crucial tool to evaluate combinatorial therapies, optimal drug concentrations and treatment dosages.

show abstract

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

Cited by 27 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

ReN VM spheroids in matrix: A neural progenitor three-dimensional in vitro model reveals DYRK1A inhibitors as potential regulators of radio-sensitivity

Contact Info

Product

Resources

About