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Increased recruitment of bone marrow-derived cells into the brain associated with altered brain cytokine profile in senescence-accelerated mice

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Abstract

Bone marrow-derived cells enter the brain in a non-inflammatory condition through the attachments of choroid plexus and differentiate into ramified myeloid cells. Neurodegenerative conditions may be associated with altered immune-brain interaction. The senescence-accelerated mouse prone 10 (SAMP10) undergoes earlier onset neurodegeneration than C57BL/6 (B6) strain. We hypothesized that the dynamics of immune cells migrating from the bone marrow to the brain is perturbed in SAMP10 mice. We created 4 groups of radiation chimeras by intra-bone marrow-bone marrow transplantation using 2-month-old (2 mo) and 10 mo SAMP10 and B6 mice as recipients with GFP transgenic B6 mice as donors, and analyzed histologically 4 months later. In the [B6 → 10 mo SAMP10] chimeras, more ramified marrow-derived cells populated a larger number of discrete brain regions than the other chimeras, especially in the diencephalon. Multiplex cytokine assays of the diencephalon prepared from non-treated 3 mo and 12 mo SAMP10 and B6 mice revealed that 12 mo SAMP10 mice exhibited higher tissue concentrations of CXCL1, CCL11, G-CSF, CXCL10 and IL-6 than the other groups. Immunohistologically, choroid plexus epithelium and ependyma produced CXCL1, while astrocytic processes in the attachments of choroid plexus expressed CCL11 and G-CSF. The median eminence produced CXCL10, hypothalamic neurons G-CSF and tanycytes CCL11 and G-CSF. These brain cytokine profile changes in 12 mo SAMP10 mice were likely to contribute to acceleration of the dynamics of marrow-derived cells to the diencephalon. Further studies on the functions of ramified marrow-derived myeloid cells would enhance our understanding of the brain-bone marrow interaction.

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Acknowledgments

We thank Ms. Takako Nagano for her technical assistance and Mr. Hilary Eastwick-Field and Ms. Keiko Ando for their help in the preparation of the manuscript. This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS, Contract Grant Nos.: 22790392 to SHI and 21590458, 24650190 and 25290020 to AS) and by Otsuka Pharmaceutical Company, Ltd.

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The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Pathology, Aichi Human Service Center, Institute for Developmental Research, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan

    Sanae Hasegawa-Ishii & Atsuyoshi Shimada

  2. Japan Society for the Promotion of Science, 5-3-1 Koujimachi, Chiyoda, Tokyo, 102-0083, Japan

    Sanae Hasegawa-Ishii

  3. First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan

    Muneo Inaba

  4. Department of Stem Cell Disorders, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan

    Ming Li, Ming Shi & Susumu Ikehara

  5. Department of Geriatrics, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Hiroyuki Umegaki

  6. Department of Pathology and Laboratory Medicine, Central Hospital, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan

    Atsuyoshi Shimada

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  1. Sanae Hasegawa-Ishii
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Correspondence to Atsuyoshi Shimada.

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429_2014_987_MOESM1_ESM.tif

Supplementary Fig. 1 Double immunofluorescence stainings of the [B6 → 10 mo SAMP10] chimeras to identify the differentiation of ramified marrow-derived cells in the brain. Ramified marrow-derived cells expressed Iba-1 (a), a myeloid marker, but not GFAP (b), an astrocyte marker, CNPase (c), an oligodendrocyte marker, or MAP2 (d), a neuronal marker. Ramified marrow-derived cells intertwined with pre-existing parenchymal astrocytes (b) and made contact with oligodendrocytic processes (c) and neuronal dendrites (d) by their fine cytoplasmic processes. Interestingly, ramified marrow-derived cells (a, arrow) kept their distance from pre-existing microglia (a, arrow head). Scale bars, 20 μm (TIFF 9884 kb)

429_2014_987_MOESM2_ESM.tif

Supplementary Fig. 2 Double immunofluorescence staining for CCL11 and SOX-2. CCL11-immunopositive cells (a) with cell bodies located in the ependymal layer of the ventral part of the third ventricle were double-immunopositive for SOX-2 in the nuclei (b), indicative of tanycytes in 12 mo SAMP10 mice. Bars, 50 μm (TIFF 6033 kb)

429_2014_987_MOESM3_ESM.tif

Supplementary Fig. 3 CCL11 and G-CSF expression in the stria terminalis. CCL11 (a) and G-CSF (b) were expressed in fiber bundles of the stria terminalis near the attachments of choroid plexus in 12 mo SAMP10 mice. These bundles consisted of elongated astrocytic cytoplasmic processes. LV, lateral ventricle; ST, stria terminalis. Scale bars, 50 μm (TIFF 3656 kb)

429_2014_987_MOESM4_ESM.tif

Supplementary Fig. 4 G-CSF expression in the hypothalamus. Immunohistochemical staining for G-CSF revealed that G-CSF was expressed in neuronal cell bodies and cytoplasmic processes in the arcuate nucleus. Larger numbers of neurons expressed G-CSF more intensively in 12 mo SAMP10 mice (b) than in 12 mo B6 mice (a). Scale bars, 20 μm (TIFF 3629 kb)

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Hasegawa-Ishii, S., Inaba, M., Li, M. et al. Increased recruitment of bone marrow-derived cells into the brain associated with altered brain cytokine profile in senescence-accelerated mice. Brain Struct Funct 221, 1513–1531 (2016). https://doi.org/10.1007/s00429-014-0987-2

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