Bone marrow drives central nervous system regeneration after radiation injury

Dietrich, Jörg; Baryawno, Ninib; Nayyar, Naema; Valtis, Yannis K.; Yang, Bishan; Ly, Ina; Besnard, Antoine; Sévère, Nicolas; Gustafsson, Karin; Andronesi, Ovidiu C.; Batchelor, Tracy T.; Sahay, Amar; Scadden, David T.

doi:10.1172/jci90647

Cited by 36 publications

(21 citation statements)

References 65 publications

(51 reference statements)

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“…Pathway analysis of these modules reveals mechanisms involving cilium organization and assembly. A recent study using granulocyte colony-stimulating factor (G-CSF) receptor knockout mice and BM transplant show that BM cells (responding to G-CSF) home to the irradiated brain and promote brain repair and neural progenitor cell proliferation [ 86 ]. Recent reports have demonstrated that brain-engrafted monocytes exhibit a distinct gene signature compared to microglia [ 22 , 82 ].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…During development of the embryo, tissues are seeded with successive waves of hematopoietic precursors from the yolk sac and fetal liver 1 , 6 – 8 , which following birth are displaced by BM-derived monocytes in some organs 9 – 14 . Furthermore, upon infection or injury, circulating blood monocytes can give rise to long-lived replacements of macrophages in many organs including the heart 15 , liver 16 , lung 17 , and brain 18 , 19 . The final macrophage composition can thus be heterogeneous across organs, and this has complicated recent attempts to assign macrophage nomenclature based on their ontogeny 20 .…”

Section: Introductionmentioning

confidence: 99%

“…Significant reprogramming of macrophage precursors transplanted into adult tissue microenvironments has been demonstrated 24 , 26 , 27 , arguing for an imprinting capacity of the macrophage niche as was recently proposed 28 . Peripheral myeloid cells that colonize the microglial niche adopt microglia-like morphology 29 , 30 , display ATP-sensing capacity 29 , can promote repair following cranial irradiation 19 and require TGF-β signaling for functional integration into the central nervous system (CNS) 31 . However, to what degree monocytes become imprinted by the microglial niche and what factors regulate this imprinting remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells

et al. 2018

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Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

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“…Recently, Dietrich et al using a granulocyte-colony stimulating factor (G-CSF) knockout receptor model of mice, reported a relationship between the bone marrow and the brain, following radiation exposure [10]. In particular, it was found that bone marrow monocytes and macrophages are necessary for the restoration of structural and functional disorders, including the regeneration of white matter, the brain and the improvement of neurocognitive functions.…”

Section: Introductionmentioning

confidence: 99%

“…In particular, it was found that bone marrow monocytes and macrophages are necessary for the restoration of structural and functional disorders, including the regeneration of white matter, the brain and the improvement of neurocognitive functions. The authors demonstrated that bone marrow G-CSF is critical for repairing damaged brain cells [10]. Therefore, certain differences in the induction and in the restoration of brain damage are anticipated during local exposure of the skull and whole body to IR, inducing damage to the brain and blood-forming system simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-ray Irradiation

Abdullaev

Gubina

Bulanova

et al. 2020

IJMS

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Studies of molecular changes occurred in various brain regions after whole-body irradiation showed a significant increase in terms of the importance in gaining insight into how to slow down or prevent the development of long-term side effects such as carcinogenesis, cognitive impairment and other pathologies. We have analyzed nDNA damage and repair, changes in mitochondrial DNA (mtDNA) copy number and in the level of mtDNA heteroplasmy, and also examined changes in the expression of genes involved in the regulation of mitochondrial biogenesis and dynamics in three areas of the rat brain (hippocampus, cortex and cerebellum) after whole-body X-ray irradiation. Long amplicon quantitative polymerase chain reaction (LA-QPCR) was used to detect nDNA and mtDNA damage. The level of mtDNA heteroplasmy was estimated using Surveyor nuclease technology. The mtDNA copy numbers and expression levels of a number of genes were determined by real-time PCR. The results showed that the repair of nDNA damage in the rat brain regions occurs slowly within 24 h; in the hippocampus, this process runs much slower. The number of mtDNA copies in three regions of the rat brain increases with a simultaneous increase in mtDNA heteroplasmy. However, in the hippocampus, the copy number of mutant mtDNAs increases significantly by the time point of 24 h after radiation exposure. Our analysis shows that in the brain regions of irradiated rats, there is a decrease in the expression of genes (ND2, CytB, ATP5O) involved in ATP synthesis, although by the same time point after irradiation, an increase in transcripts of genes regulating mitochondrial biogenesis is observed. On the other hand, analysis of genes that control the dynamics of mitochondria (Mfn1, Fis1) revealed that sharp decrease in gene expression level occurred, only in the hippocampus. Consequently, the structural and functional characteristics of the hippocampus of rats exposed to whole-body radiation can be different, most significantly from those of the other brain regions.

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Bone marrow drives central nervous system regeneration after radiation injury

Cited by 36 publications

References 65 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

Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells

Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-ray Irradiation

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