Treatment of a genetic brain disease by CNS-wide microglia replacement
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- Yohei Shibuya
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Kevin K. Kumar
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Marius Marc-Daniel Mader
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Yongjin Yoo
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Luis Angel Ayala
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Mu Zhou
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Manuel Alexander Mohr
- Department of Biology, Stanford University, Stanford, CA 94305, USA.
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- Gernot Neumayer
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Ishan Kumar
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Ryo Yamamoto
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Paul Marcoux
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Benjamin Liou
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
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- F. Chris Bennett
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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- Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Ying Sun
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
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- Xiaoke Chen
- Department of Biology, Stanford University, Stanford, CA 94305, USA.
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- Frank L. Heppner
- Department of Neuropathology, Cluster of Excellence, NeuroCure, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany.
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- Tony Wyss-Coray
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Thomas C. Südhof
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Marius Wernig
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Description
<jats:p>Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.</jats:p>
Journal
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- Science Translational Medicine
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Science Translational Medicine 14 (636), eabl9945-, 2022-03-16
American Association for the Advancement of Science (AAAS)
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Details 詳細情報について
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- CRID
- 1360298761831424768
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- ISSN
- 19466242
- 19466234
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- Data Source
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- Crossref