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Research Article

Migration-based selections of antibodies that convert bone marrow into trafficking microglia-like cells that reduce brain amyloid β

Kyung Ho Han, Britni M. Arlian, Matthew S. Macauley, James C. Paulson, and Richard A. Lerner
  1. aDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
  2. bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;
  3. cDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037

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PNAS January 16, 2018 115 (3) E372-E381; first published January 2, 2018; https://doi.org/10.1073/pnas.1719259115
Kyung Ho Han
aDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
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Britni M. Arlian
bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;
cDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037
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Matthew S. Macauley
bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;
cDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037
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James C. Paulson
bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;
cDepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037
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Richard A. Lerner
aDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
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  • For correspondence: rlerner@scripps.edu
  1. Contributed by Richard A. Lerner, December 4, 2017 (sent for review November 6, 2017; reviewed by David M. Holtzman and Bradley T. Hyman)

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Significance

A migration-based selection system is used to identify antibodies from combinatorial libraries that induce stem cells to both differentiate and selectively traffic to different tissues in adult animals. Significantly, a single agonist antibody induces microglia-like cells, which have the capacity to migrate to the brain and decrease amyloid beta deposition in the brain.

Abstract

One goal of regenerative medicine is to repair damaged tissue. This requires not only generating new cells of the proper phenotype, but also selecting for those that properly integrate into sites of injury. In our laboratory we are using a cell-migration–based in vivo selection system to generate antibodies that induce cells to both differentiate and selectively localize to different tissues. Here we describe an antibody that induces bone marrow stem cells to differentiate into microglia-like cells that traffic to the brain where they organize into typical networks. Interestingly, in the APP/PS1 Alzheimer’s disease mouse model, these induced microglia-like cells are found at sites of plaque formation and significantly reduce their number. These results raise the intriguing question as to whether one can use such antibody-induced differentiation of stem cells to essentially recapitulate embryogenesis in adults to discover cells that can regenerate damaged organ systems.

  • antibody
  • stem cell
  • microglia
  • Alzheimer’s disease

Footnotes

  • ↵1To whom correspondence should be addressed. Email: rlerner{at}scripps.edu.
  • Author contributions: K.H.H. and R.A.L. designed research; K.H.H. and B.M.A. performed research; M.S.M. contributed new reagents/analytic tools; K.H.H. and J.C.P. analyzed data; and K.H.H. and R.A.L. wrote the paper.

  • Reviewers: D.M.H., Washington University School of Medicine; and B.T.H., Massachusetts General Hospital/Harvard Medical School.

  • The authors declare no conflict of interest.

  • Data deposition: Raw data from RNA-seq analyses have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107006 (accession no. GSE107006).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1719259115/-/DCSupplemental.

  • Copyright © 2018 the Author(s). Published by PNAS.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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Trafficking microglia-like cells reduce amyloid β
Kyung Ho Han, Britni M. Arlian, Matthew S. Macauley, James C. Paulson, Richard A. Lerner
Proceedings of the National Academy of Sciences Jan 2018, 115 (3) E372-E381; DOI: 10.1073/pnas.1719259115

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Trafficking microglia-like cells reduce amyloid β
Kyung Ho Han, Britni M. Arlian, Matthew S. Macauley, James C. Paulson, Richard A. Lerner
Proceedings of the National Academy of Sciences Jan 2018, 115 (3) E372-E381; DOI: 10.1073/pnas.1719259115
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Proceedings of the National Academy of Sciences: 115 (3)
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