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 December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):281-293. https://doi.org/10.1172/JCI90647.
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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 2

Characterization of G-CSFR expression in the adult CNS.

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Characterization of G-CSFR expression in the adult CNS. (A) CNS regions ...
(A) CNS regions assessed for G-CSF receptor expression. (B) G-CSF receptor expression in different areas of the CNS as shown by immunofluorescence. Original magnification, ×20 (upper panels); ×40 (lower panels). (C) Quantification of G-CSF receptor–positive cells from B. n = 6 independent biological replicates. Data are presented as mean ± SEM of biological replicates. (D) Characterization of cultured Nestin+ cells. Immunofluorescence staining of cultured Nestin+ cells for G-CSF receptor (green) and Nestin (red). Original magnification, ×40. (E) Cultured Nestin+ cells in the presence of increasing concentrations of G-CSF, showing an increase of cell proliferation as measured by BrdU uptake in a dose-dependent manner in the range of 1–10 μM. Cells were kept in culture for 2 to 3 days, and growth kinetics and the number of BrdU+ cells (shown as %BrdU+ cells from controls) were analyzed in the presence of increasing G-CSF concentrations in 4 independent experiments. SWM, subcortical white matter.