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Efficient replacement

Cell therapies have the potential of being an effective approach for treating neurodegenerative conditions. However, the need for local delivery and the poor distribution of the transplanted cells hinder the development of effective treatments. Here, Shibuya et al. developed an efficient microglia replacement approach in rodents using circulation-derived myeloid cells (CDMCs). The cells broadly incorporated in the brain and generated microglia-like cells more efficiently than bone marrow transplant. In a mouse model of progressive neurodegeneration, CDMC-mediated microglia replacement reduced cell loss and brain inflammation, improved motor behavior, and extended life span. The results suggest that this approach might be therapeutic in multiple neurological conditions.

Abstract

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.

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References (6269)

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Published In

Science Translational Medicine
Volume 14 | Issue 636
March 2022

Submission history

Received: 19 August 2021
Accepted: 10 February 2022

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Acknowledgments

We would like to thank all members of the Wernig laboratory, J. Pluvinage, D. Mochly-Rosen, and K. Grimes for helpful discussions throughout the project and T. Broer, M. R. Casilla, FACS core at Institute for Stem Cell Biology and Regenerative Medicine, and Stanford Neuroscience Microscopy Service (supported by NIH NS069375) for technical support.
Funding: The project was supported by a pilot grant from the Stanford Alzheimer’s Disease Research Center NIH grant (P50AG047366 to M.W.), Howard Hughes Medical Institute Faculty Scholar Award, and the Goldman-Sachs Foundation to M.W. Y. Shibuya was supported by the Larry L. Hillblom Foundation Postdoctoral Fellowship (2017-A-016-FEL). K.K.K. was supported by the Stanford Neurosurgery Resident Research Education Program R25 (NIH NS065741-10). M.M.-D.M. was supported by Deutsche Forschungsgemeinschaft (DFG) (MA 8492/1-1). Y.Y. was supported by the New York Stem Cell Foundation Druckenmiller Fellowship (NYSCF–D–F74). L.A.A. was supported by grants from the NIH and California Institute of Regenerative Medicine (CIRM) awarded to L.A.A.’s home institution, San Francisco State University (R25-GM059298, CIRM:EDUC2-08391).
Author contributions: Study concept and design: Y. Shibuya and M.W. BMT and posttransplantation analyses: Y. Shibuya, K.K.K., M.M.-D.M., Y.Y., L.A.A., I.K., R.Y., and P.M. RNA-seq data processing: Y.Y. Two-photon microscopy: M.M.-D.M. and M.A.M. Droplet digital PCR: G.N. Behavioral tests: K.K.K. and M.Z. Development and maintenance of Psap-deficient mice: B.L. and Y. Sun. Supervision and suggestions on data interpretation: T.C.S., T.W.-C., F.L.H., X.C., Y. Sun, H.N., and F.C.B. Drafting of original manuscript: Y. Shibuya and M.W. All authors reviewed, revised, and approved the final version of the paper.
Competing interests: The authors declare that they have no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. The bulk RNA-seq dataset generated in this study is available at the NCBI BioProject (www.ncbi.nlm.nih.gov/bioproject), accession no: PRJNA600501. PLX5622 was provided by Plexxikon Inc. under a material transfer agreement between Stanford University and Plexxikon Inc.

Authors

Affiliations

Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Yongjin Yoo
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Gernot Neumayer
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ryo Yamamoto
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Paul Marcoux
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Benjamin Liou
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
F. Chris Bennett
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Ying Sun
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Neuropathology, Cluster of Excellence, NeuroCure, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany.
Department of Neuropathology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
Berlin Institute of Health (BIH), 10117 Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Veterans Administration Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Funding Information

Goldman-Sachs Foundation

Notes

*Corresponding author. Email: [email protected]
These authors contributed equally to this work.
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