Bone marrow drives central nervous system regeneration after radiation injury
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
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
View: Text | PDF | Corrigendum
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

×

Figure 5

Identification, quantification, and phenotype of transplanted GFP+ bone marrow cells in the mouse brain following irradiation over time.

Options: View larger image (or click on image) Download as PowerPoint
Identification, quantification, and phenotype of transplanted GFP+ bone ...
(A–D) Identification of transplanted GFP+ bone marrow cells in the murine CNS 4 weeks after transplantation. (A and B) Immunohistochemical assessment of different brain regions from mice transplanted with GFP+ bone marrow cells (transgenic UBI-GFP reporter mouse). Whole bone marrow cells from UBI-GFP mice were harvested and transplanted (1 × 106 cells/mouse) into either whole-body–irradiated (9.5 Gy) recipients or nonirradiated controls by tail-vein injection. Four weeks after irradiation, mice were sacrificed and brains sectioned for immunohistochemical evidence of GFP+ donor cells. Original magnification, ×10 (A); ×40 (B). (C) CNS regions assessed by immunofluorescence for GFP+ bone marrow cells, colabeled with the microglial marker Iba-1. Original magnification, ×20, except ×10 for perivascular region upper panel, choroid plexus upper panel, and DG lower panel. (D) Quantification of Iba-1+GFP+ cells from C. n = 3 independent biological replicates. Data are presented as mean ± SEM of biological replicates.