Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Michael-John Dolan; Martine Therrien; Saša Jereb; Tushar Kamath; Vahid Gazestani; Trevor Atkeson; Samuel E Marsh; Aleksandrina Goeva; Neal M Lojek; Sarah Murphy; Cassandra M White; Julia Joung; Bingxu Liu; Francesco Limone; Kevin Eggan; Nir Hacohen; Bradley E Bernstein; Christopher K Glass; Ville Leinonen; Mathew Blurton-Jones; Feng Zhang; Charles B Epstein; Evan Z Macosko; Beth Stevens

doi:10.1038/s41590-023-01558-2

Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Nat Immunol. 2023 Aug;24(8):1382-1390. doi: 10.1038/s41590-023-01558-2. Epub 2023 Jul 27.

Authors

Michael-John Dolan^#^{1

2

3}, Martine Therrien^#^{1

2

3}, Saša Jereb^{1

2

3}, Tushar Kamath^{1

3}, Vahid Gazestani¹, Trevor Atkeson¹, Samuel E Marsh^{2

3}, Aleksandrina Goeva¹, Neal M Lojek¹, Sarah Murphy², Cassandra M White⁴, Julia Joung^{4

5

6

7

8}, Bingxu Liu⁴, Francesco Limone^{1

9

10}, Kevin Eggan^{1

9}, Nir Hacohen^{4

11

12}, Bradley E Bernstein^{4

13

14

15}, Christopher K Glass¹⁶, Ville Leinonen¹⁷, Mathew Blurton-Jones¹⁸, Feng Zhang^{4

5

6

7

8}, Charles B Epstein⁴, Evan Z Macosko^{19

20}, Beth Stevens^{21

22

23

24

25}

Affiliations

¹ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard Cambridge, Cambridge, MA, USA.
⁵ Department of Biological Engineering, MIT, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Boston, MA, USA.
⁷ Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA.
⁸ McGovern Institute for Brain Research at MIT, Cambridge, MA, USA.
⁹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
¹⁰ Leiden University Medical Center, LUMC, Leiden, the Netherlands.
¹¹ Department of Medicine, Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
¹⁵ Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁷ Department of Neurosurgery, Kuopio University Hospital and Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland.
¹⁸ Department of Neurobiology and Behavior, Sue and Bill Gross Stem Cell Research Center, UCI Institute for Memory Impairments and Neurological Disorders, Institute for Immunology, University of California, Irvine, CA, USA.
¹⁹ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. emacosko@broadinstitute.org.
²⁰ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA. emacosko@broadinstitute.org.
²¹ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Beth.Stevens@childrens.harvard.edu.
²² Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA. Beth.Stevens@childrens.harvard.edu.
²³ Harvard Medical School, Boston, MA, USA. Beth.Stevens@childrens.harvard.edu.
²⁴ Broad Institute of MIT and Harvard Cambridge, Cambridge, MA, USA. Beth.Stevens@childrens.harvard.edu.
²⁵ Howard Hughes Medical Institute, Boston, MA, USA. Beth.Stevens@childrens.harvard.edu.

^# Contributed equally.

Abstract

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer's disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

Publication types

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

MeSH terms

Alzheimer Disease* / genetics
Brain
Humans
Induced Pluripotent Stem Cells*
Microglia
Neurodegenerative Diseases*

Abstract

Publication types

MeSH terms

Grants and funding