iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Edsel M Abud; Ricardo N Ramirez; Eric S Martinez; Luke M Healy; Cecilia H H Nguyen; Sean A Newman; Andriy V Yeromin; Vanessa M Scarfone; Samuel E Marsh; Cristhian Fimbres; Chad A Caraway; Gianna M Fote; Abdullah M Madany; Anshu Agrawal; Rakez Kayed; Karen H Gylys; Michael D Cahalan; Brian J Cummings; Jack P Antel; Ali Mortazavi; Monica J Carson; Wayne W Poon; Mathew Blurton-Jones

doi:10.1016/j.neuron.2017.03.042

iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Neuron. 2017 Apr 19;94(2):278-293.e9. doi: 10.1016/j.neuron.2017.03.042.

Authors

Edsel M Abud¹, Ricardo N Ramirez², Eric S Martinez¹, Luke M Healy³, Cecilia H H Nguyen¹, Sean A Newman⁴, Andriy V Yeromin⁵, Vanessa M Scarfone⁴, Samuel E Marsh⁶, Cristhian Fimbres⁷, Chad A Caraway⁷, Gianna M Fote¹, Abdullah M Madany⁸, Anshu Agrawal⁹, Rakez Kayed¹⁰, Karen H Gylys¹¹, Michael D Cahalan⁵, Brian J Cummings¹², Jack P Antel³, Ali Mortazavi², Monica J Carson⁸, Wayne W Poon¹³, Mathew Blurton-Jones¹⁴

Affiliations

¹ Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
² Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA.
³ Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada.
⁴ Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
⁵ Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697, USA.
⁶ Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
⁷ Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
⁸ Division of Biomedical Sciences, Center for Glia-Neuronal Interactions, University of California, Riverside, Riverside, CA 92521, USA.
⁹ Department of Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
¹⁰ Department of Neurology, George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹¹ UCLA School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Anatomy and Neurobiology, University of California Irvine, Irvine, CA 92697, USA.
¹³ Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA. Electronic address: wpoon@uci.edu.
¹⁴ Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.

Abstract

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

Keywords: 3D organoids; AD-GWAS; Alzheimer’s disease; Beta-amyloid; Tau; cell models of disease; induced pluripotent stem cells; microglia; mouse transplantation; neurodegenerative diseases.

MeSH terms

Alzheimer Disease / metabolism*
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / genetics
Animals
Brain / metabolism*
Cells, Cultured
Cytokines / metabolism
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells / cytology*
Mice
Microglia / metabolism*
Peptide Fragments / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Cytokines
Peptide Fragments

Abstract

MeSH terms

Substances

Grants and funding