Bone marrow drives central nervous system regeneration after radiation injury
Jorg Dietrich, … , Amar Sahay, David T. Scadden
Jorg Dietrich, … , Amar Sahay, David T. Scadden
Published January 2, 2018; First published December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):281-293. https://doi.org/10.1172/JCI90647.
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Categories: Research Article Hematology Neuroscience

Bone marrow drives central nervous system regeneration after radiation injury

Abstract

Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow–derived monocytes and macrophages are essential for structural and functional repair mechanisms, including regeneration of cerebral white matter and improvement in neurocognitive function. Using a granulocyte-colony stimulating factor (G-CSF) receptor knockout mouse model in combination with bone marrow cell transplantation, MRI, and neurocognitive functional assessments, we demonstrate that bone marrow–derived G-CSF–responsive cells home to the injured brain and are critical for altering neural progenitor cells and brain repair. Additionally, compared with untreated animals, animals that received G-CSF following radiation injury exhibited enhanced functional brain repair. Together, these results demonstrate that, in addition to its known role in defense and debris removal, the hematopoietic system provides critical regenerative drive to the brain that can be modulated by clinically available agents.

Authors

Jorg Dietrich, Ninib Baryawno, Naema Nayyar, Yannis K. Valtis, Betty Yang, Ina Ly, Antoine Besnard, Nicolas Severe, Karin U. Gustafsson, Ovidiu C. Andronesi, Tracy T. Batchelor, Amar Sahay, David T. Scadden

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Figure 6

Immunohistochemical assessment of different brain regions from mice transplanted with GFP+ bone marrow cells (transgenic UBI-GFP reporter mouse) and assessed 2 and 8 weeks after irradiation.

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Immunohistochemical assessment of different brain regions from mice tran...
(A) Mice were sacrificed and brains sectioned for immunohistochemical evidence of GFP+ donor cells. Original magnification, ×20 (CC and DG); ×40 (choroid plexus and perivascular region). n = 3 independent biological replicates. Data are presented as mean ± SEM. (B) Quantification of GFP+ cells in different brain regions evaluated at 2 and 8 weeks after irradiation showing a significant increase in the total number of GFP+ cells after 8 weeks in CC, DG, SVZ, and cortex. (C and D) Significant change in morphology of GFP+ cells over time with signs of cellular maturation and increase in branched morphology in various regions. Original magnification, ×40, except ×60 in DG and perivascular region, left-sided panel. (E–G) Phenotypical analysis of GFP+ cells demonstrate that the majority of cells colabel the microglial marker Iba-1 (see Figure 5C) and the monocyte-macrophage marker F4/80. Upper panel original magnification: ×20. Lower panel original magnification: ×40 (E). In addition, many GFP+ cells colabeled with B-III tubulin Upper panel original magnification: ×20. Lower panel original magnification: ×40 (F). (G) Quantification of GFP+ cells colabeling with Iba-1, F4/80, and B-III tubulin. Asterisks indicate a significant change relative to control. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA. n = 3 mice/group. Data are presented as mean ± SEM of biological replicates.