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

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 MortazaviMonica J. Carson, Wayne W. Poon, Mathew Blurton-Jones

Neurology

Research output: Contribution to journal › Article › peer-review

756 Scopus citations

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.

Original language	English (US)
Pages (from-to)	278-293.e9
Journal	Neuron
Volume	94
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2017.03.042
State	Published - Apr 19 2017

Keywords

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

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2017.03.042

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Abud, E. M., Ramirez, R. N., Martinez, E. S., Healy, L. M., Nguyen, C. H. H., Newman, S. A., Yeromin, A. V., Scarfone, V. M., Marsh, S. E., Fimbres, C., Caraway, C. A., Fote, G. M., Madany, A. M., Agrawal, A., Kayed, R., Gylys, K. H., Cahalan, M. D., Cummings, B. J., Antel, J. P., ... Blurton-Jones, M. (2017). iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron, 94(2), 278-293.e9. https://doi.org/10.1016/j.neuron.2017.03.042

Abud, EM, Ramirez, RN, Martinez, ES, Healy, LM, Nguyen, CHH, Newman, SA, Yeromin, AV, Scarfone, VM, Marsh, SE, Fimbres, C, Caraway, CA, Fote, GM, Madany, AM, Agrawal, A, Kayed, R, Gylys, KH, Cahalan, MD, Cummings, BJ, Antel, JP, Mortazavi, A, Carson, MJ, Poon, WW & Blurton-Jones, M 2017, 'iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases', Neuron, vol. 94, no. 2, pp. 278-293.e9. https://doi.org/10.1016/j.neuron.2017.03.042

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title = "iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases",

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",

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

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year = "2017",

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day = "19",

doi = "10.1016/j.neuron.2017.03.042",

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AU - Abud, Edsel M.

AU - Ramirez, Ricardo N.

AU - Martinez, Eric S.

AU - Healy, Luke M.

AU - Nguyen, Cecilia H.H.

AU - Newman, Sean A.

AU - Yeromin, Andriy V.

AU - Scarfone, Vanessa M.

AU - Marsh, Samuel E.

AU - Fimbres, Cristhian

AU - Caraway, Chad A.

AU - Fote, Gianna M.

AU - Madany, Abdullah M.

AU - Agrawal, Anshu

AU - Kayed, Rakez

AU - Gylys, Karen H.

AU - Cahalan, Michael D.

AU - Cummings, Brian J.

AU - Antel, Jack P.

AU - Mortazavi, Ali

AU - Carson, Monica J.

AU - Poon, Wayne W.

AU - Blurton-Jones, Mathew

PY - 2017/4/19

Y1 - 2017/4/19

N2 - 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.

AB - 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.

KW - 3D organoids

KW - AD-GWAS

KW - Alzheimer's disease

KW - Beta-amyloid

KW - Tau

KW - cell models of disease

KW - induced pluripotent stem cells

KW - microglia

KW - mouse transplantation

KW - neurodegenerative diseases

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DO - 10.1016/j.neuron.2017.03.042

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VL - 94

SP - 278-293.e9

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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