Functional endothelial progenitor cells selectively recruit neurovascular protective monocyte-derived F4/80+/Ly6c+ macrophages in a mouse model of retinal degeneration

Authors

  • Shinichi Fukuda,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
    2. Department of Ophthalmology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
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  • Masumi Nagano,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
    2. MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Toshiharu Yamashita,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
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  • Kenichi Kimura,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
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  • Ikki Tsuboi,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
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  • Georgina Salazar,

    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
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  • Shinji Ueno,

    1. Department of Ophthalmology, Graduate School of Medicine, University of Nagoya, Nagoya, Japan
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  • Mineo Kondo,

    1. Department of Ophthalmology, Graduate School of Medicine University of Mie, Tsu City, Mie, Japan
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  • Tilo Kunath,

    1. MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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  • Tetsuro Oshika,

    1. Department of Ophthalmology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
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  • Osamu Ohneda

    Corresponding author
    1. Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science
    • Correspondence: Osamu Ohneda, M.D., Ph.D., Department of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305–8575, Japan. Telephone: +81-29-853-2938; Fax: +81-29-853-2938; e-mail: oohneda@md.tsukuba.ac.jp

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  • Author contributions: S.F.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.N.: conception and design, administrative support, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; T.Y.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; K.K. and I.T.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; G.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; S.U.: provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; M.K.: provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; T.K.: data analysis and interpretation, manuscript writing, and final approval of manuscript; T.O.: conception and design, financial support, administrative support, and final approval of manuscript; O.O.: conception and design, financial support, administrative support, provision of study material or patients, data analysis and interpretation, manuscript writing, and final approval of manuscript.

ABSTRACT

Retinitis pigmentosa is a group of inherited eye disorders that result in profound vision loss with characteristic retinal neuronal degeneration and vasculature attenuation. In a mouse model of retinitis pigmentosa, endothelial progenitor cells (EPC) from bone marrow rescued the vasculature and photoreceptors. However, the mechanisms and cell types underlying these protective effects were uncertain. We divided EPC, which contribute to angiogenesis, into two subpopulations based on their aldehyde dehydrogenase (ALDH) activity and observed that EPC with low ALDH activity (Alde-Low) had greater neuroprotection and vasoprotection capabilities after injection into the eyes of an rd1 mouse model of retinitis pigmentosa compared with EPC with high ALDH activity (Alde-High). Of note, Alde-Low EPC selectively recruited F4/80+/Ly6c+ monocyte-derived macrophages from bone marrow into retina through CCL2 secretion. In addition, the mRNA levels of CCR2, the neurotrophic factors TGF-β1 and IGF-1, and the anti-inflammatory mediator interleukin-10 were higher in migrated F4/80+/Ly6c+ monocyte-derived macrophages as compared with F4/80+/Ly6c resident retinal microglial cells. These results suggest a novel therapeutic approach using EPC to recruit neuroprotective macrophages that delay the progression of neural degenerative disease. Stem Cells 2013;31:2149–2161

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