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 1

In vivo effects of G-CSF in irradiated mice.

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In vivo effects of G-CSF in irradiated mice. (A) Immunohistochemical ass...
(A) Immunohistochemical assessment of BrdU+ neural progenitors in the lateral SVZ and DG of the brain from mice treated with PBS or G-CSF or whole-body–irradiated mice (4.5 Gy) treated with PBS or G-CSF. G-CSF was injected on days 1, 3, and 5 after irradiation. At day 5, BrdU was injected, and mice were sacrificed 2 hours after injection. Original magnification: ×20. (B) Quantification of BrdU+ cells from the SVZ, DG, and CC. Asterisks indicate a significant change relative to control. *P < 0.05; ***P < 0.001; ****P < 0.0001, 2-way ANOVA. n = 6–8 independent biological replicates. Data are presented as mean ± SEM of biological replicates. (C) Quantification of Nestin+ cells in the brain (SVZ and DG) of nonirradiated mice treated with G-CSF. Asterisks indicate a significant change relative to control. *P < 0.05; ***P < 0.001, Student’s t test. n = 3 independent biological replicates. Data are presented as mean ± SEM of biological replicates.