Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Jonathan Hasselmann; Morgan A Coburn; Whitney England; Dario X Figueroa Velez; Sepideh Kiani Shabestari; Christina H Tu; Amanda McQuade; Mahshad Kolahdouzan; Karla Echeverria; Christel Claes; Taylor Nakayama; Ricardo Azevedo; Nicole G Coufal; Claudia Z Han; Brian J Cummings; Hayk Davtyan; Christopher K Glass; Luke M Healy; Sunil P Gandhi; Robert C Spitale; Mathew Blurton-Jones

doi:10.1016/j.neuron.2019.07.002

Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Neuron. 2019 Sep 25;103(6):1016-1033.e10. doi: 10.1016/j.neuron.2019.07.002. Epub 2019 Jul 30.

Authors

Jonathan Hasselmann¹, Morgan A Coburn¹, Whitney England², Dario X Figueroa Velez³, Sepideh Kiani Shabestari⁴, Christina H Tu⁴, Amanda McQuade¹, Mahshad Kolahdouzan⁵, Karla Echeverria⁴, Christel Claes⁴, Taylor Nakayama³, Ricardo Azevedo³, Nicole G Coufal⁶, Claudia Z Han⁷, Brian J Cummings⁴, Hayk Davtyan⁸, Christopher K Glass⁹, Luke M Healy⁵, Sunil P Gandhi¹⁰, Robert C Spitale¹¹, Mathew Blurton-Jones¹²

Affiliations

¹ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92696, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92696, USA.
² Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA.
³ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA.
⁴ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92696, USA.
⁵ Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada.
⁶ Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
⁷ Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, USA.
⁸ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92696, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92696, USA.
⁹ Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, USA; Department of Medicine, University of California, San Diego, San Diego, CA 92093-0651, USA.
¹⁰ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
¹¹ Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
¹² Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92696, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92696, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92696, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.

Abstract

iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.

Keywords: Alzheimer’s disease; TREM-2; beta-amyloid; chimera; hematopoietic; humanized; microglia; neurodegeneration; pluripotent; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Alzheimer Disease / genetics*
Amyloid beta-Peptides / metabolism*
Animals
Brain / cytology
Brain / metabolism*
Cell Differentiation*
Disease Models, Animal
Gene Expression*
Granulocyte-Macrophage Colony-Stimulating Factor / genetics
Hematopoietic Stem Cell Transplantation
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Macrophage Colony-Stimulating Factor / genetics
Mice
Mice, Transgenic
Microglia / cytology
Microglia / metabolism*
Plaque, Amyloid / genetics*
Thrombopoietin / genetics
Transplantation Chimera*

Substances

Amyloid beta-Peptides
CSF1 protein, human
CSF2 protein, human
Macrophage Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Thrombopoietin

Abstract

Publication types

MeSH terms

Substances

Grants and funding