Emerging Models to Study Human Microglia In Vitro

Overview

Journal Adv Neurobiol

Publisher Springer

Date 2024 Aug 29

PMID 39207712

Authors

Henna Jantti

Lois Kistemaker

Alice Buonfiglioli

Lot D de Witte

Tarja Malm

Elly M Hol

Affiliations

Soon will be listed here.

Abstract

New in vitro models provide an exciting opportunity to study live human microglia. Previously, a major limitation in understanding human microglia in health and disease has been their limited availability. Here, we provide an overview of methods to obtain human stem cell or blood monocyte-derived microglia-like cells that provide a nearly unlimited source of live human microglia for research. We address how understanding microglial ontogeny can help modeling microglial identity and function in a dish with increased accuracy. Moreover, we categorize stem cell-derived differentiation methods into embryoid body based, growth factor driven, and coculture-driven approaches, and review novel viral approaches to reprogram stem cells directly into microglia-like cells. Furthermore, we review typical readouts used in the field to verify microglial identity and characterize functional microglial phenotypes. We provide an overview of methods used to study microglia in environments more closely resembling the (developing) human CNS, such as cocultures and brain organoid systems with incorporated or innately developing microglia. We highlight how microglia-like cells can be utilized to reveal molecular and functional mechanisms in human disease context, focusing on Alzheimer's disease and other neurodegenerative diseases as well as neurodevelopmental diseases. Finally, we provide a critical overview of challenges and future opportunities to more accurately model human microglia in a dish and conclude that novel in vitro microglia-like cells provide an exciting potential to bring preclinical research of microglia to a new era.

References

Abud E, Ramirez R, Martinez E, Healy L, Nguyen C, Newman S . iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron. 2017; 94(2):278-293.e9. PMC: 5482419. DOI: 10.1016/j.neuron.2017.03.042. View

Akiyama H, Jalloh S, Park S, Lei M, Mostoslavsky G, Gummuluru S . Expression of HIV-1 Intron-Containing RNA in Microglia Induces Inflammatory Responses. J Virol. 2020; 95(5). PMC: 8092841. DOI: 10.1128/JVI.01386-20. View

Allison R, Adelman J, Abrudan J, Urrutia R, Zimmermann M, Mathison A . Microglia Influence Neurofilament Deposition in ALS iPSC-Derived Motor Neurons. Genes (Basel). 2022; 13(2). PMC: 8871895. DOI: 10.3390/genes13020241. View

Alsema A, Jiang Q, Kracht L, Gerrits E, Dubbelaar M, Miedema A . Profiling Microglia From Alzheimer's Disease Donors and Non-demented Elderly in Acute Human Postmortem Cortical Tissue. Front Mol Neurosci. 2020; 13:134. PMC: 7655794. DOI: 10.3389/fnmol.2020.00134. View

Alvarez-Carbonell D, Ye F, Ramanath N, Garcia-Mesa Y, Knapp P, Hauser K . Cross-talk between microglia and neurons regulates HIV latency. PLoS Pathog. 2019; 15(12):e1008249. PMC: 6953890. DOI: 10.1371/journal.ppat.1008249. View

Amos P, Fung S, Case A, Kifelew J, Osnis L, Smith C . Modulation of Hematopoietic Lineage Specification Impacts TREM2 Expression in Microglia-Like Cells Derived From Human Stem Cells. ASN Neuro. 2017; 9(4):1759091417716610. PMC: 5548325. DOI: 10.1177/1759091417716610. View

Andreone B, Przybyla L, Llapashtica C, Rana A, Davis S, van Lengerich B . Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23(8):927-938. DOI: 10.1038/s41593-020-0650-6. View

Ao Z, Cai H, Wu Z, Song S, Karahan H, Kim B . Tubular human brain organoids to model microglia-mediated neuroinflammation. Lab Chip. 2021; 21(14):2751-2762. PMC: 8493632. DOI: 10.1039/d1lc00030f. View

Bartalska K, Hubschmann V, Korkut-Demirbas M, Cubero R, Venturino A, Rossler K . A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation. iScience. 2022; 25(7):104580. PMC: 9250027. DOI: 10.1016/j.isci.2022.104580. View

10.

Beins E, Ulas T, Ternes S, Neumann H, Schultze J, Zimmer A . Characterization of inflammatory markers and transcriptome profiles of differentially activated embryonic stem cell-derived microglia. Glia. 2016; 64(6):1007-20. DOI: 10.1002/glia.22979. View

11.

Bennett M, Bennett F, Liddelow S, Ajami B, Zamanian J, Fernhoff N . New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A. 2016; 113(12):E1738-46. PMC: 4812770. DOI: 10.1073/pnas.1525528113. View

12.

Beutner C, Roy K, Linnartz B, Napoli I, Neumann H . Generation of microglial cells from mouse embryonic stem cells. Nat Protoc. 2010; 5(9):1481-94. DOI: 10.1038/nprot.2010.90. View

13.

Bian Z, Gong Y, Huang T, Lee C, Bian L, Bai Z . Deciphering human macrophage development at single-cell resolution. Nature. 2020; 582(7813):571-576. DOI: 10.1038/s41586-020-2316-7. View

14.

Bohlen C, Bennett F, Tucker A, Collins H, Mulinyawe S, Barres B . Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures. Neuron. 2017; 94(4):759-773.e8. PMC: 5523817. DOI: 10.1016/j.neuron.2017.04.043. View

15.

Butovsky O, Jedrychowski M, Moore C, Cialic R, Lanser A, Gabriely G . Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2013; 17(1):131-43. PMC: 4066672. DOI: 10.1038/nn.3599. View

16.

Cerdan C, McIntyre B, Mechael R, Levadoux-Martin M, Yang J, Lee J . Activin A promotes hematopoietic fated mesoderm development through upregulation of brachyury in human embryonic stem cells. Stem Cells Dev. 2012; 21(15):2866-77. PMC: 3464075. DOI: 10.1089/scd.2012.0053. View

17.

Cheng X, Huber T, Chen V, Gadue P, Keller G . Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Development. 2008; 135(20):3447-58. PMC: 3039875. DOI: 10.1242/dev.025916. View

18.

Choi K, Vodyanik M, Slukvin I . Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell-derived lin-CD34+CD43+CD45+ progenitors. J Clin Invest. 2009; 119(9):2818-29. PMC: 2735935. DOI: 10.1172/JCI38591. View

19.

Choi K, Vodyanik M, Slukvin I . Hematopoietic differentiation and production of mature myeloid cells from human pluripotent stem cells. Nat Protoc. 2011; 6(3):296-313. PMC: 3066067. DOI: 10.1038/nprot.2010.184. View

20.

Choi K, Vodyanik M, Togarrati P, Suknuntha K, Kumar A, Samarjeet F . Identification of the hemogenic endothelial progenitor and its direct precursor in human pluripotent stem cell differentiation cultures. Cell Rep. 2012; 2(3):553-67. PMC: 3462245. DOI: 10.1016/j.celrep.2012.08.002. View