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

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

doi:10.1016/j.neuron.2017.03.042

Cited by 760 publications

(1,052 citation statements)

References 79 publications

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“…These can simply be harvested by collecting the supernatant without disrupting the EBs and replenishing flasks with fresh medium for many subsequent weekly harvests. The cumulative yield of pMacpre for the lines used in this study was 10- to 43-fold higher than the number of input iPSCs, consistent with yields previously reported for this protocol (van Wilgenburg et al., 2013), similar to a recently published hiPS-microglia protocol (typically 40-fold) (Abud et al., 2017), and 10-fold higher than two other recently published hiPS-microglia protocols (0.5- to 4-fold and 0.8- to 3-fold yields relative to input iPSCs, respectively) (Muffat et al., 2016, Pandya et al., 2017). …”

Section: Resultsmentioning

confidence: 95%

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

et al. 2017

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SummaryMicroglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB-independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co-culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co-culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology.

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Section: Resultsmentioning

confidence: 95%

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

et al. 2017

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“…Takata et al has established a protocol that specifically resembles primitive hematopoiesis and YS macrophages for further differentiation into tissue macrophage-like cells by co-culture or engraftment. 21 The iPSC-derived microglia-like cells showed transcriptome profile highly similar to that of human adult and fetal microglia, 23 and were clustered together with cultured human microglia and away from HMDM and cultured human hepatic macrophages, 18 supporting their role as a more suitable cellular source of microglia than adult hematopoiesis-derived myeloid cells.…”

Section: Generation Functional Feature and Molecular Profiling Of Ipsdmmentioning

confidence: 96%

“…Thus, IPSDM may developmentally relate to and be a good model for MYB -independent tissue resident macrophages. Indeed, several iPSC to microglia-like cell differentiation protocols were published this year using cytokines representing the main driver of microglia lineage, 18, 19 co-culture with iPSC-derived neurons 20, 21 and astrocytes, 22 or incubating with cytokines derived from those cell types 23 to recapitulate organ-specific cues. Takata et al has established a protocol that specifically resembles primitive hematopoiesis and YS macrophages for further differentiation into tissue macrophage-like cells by co-culture or engraftment.…”

Section: Generation Functional Feature and Molecular Profiling Of Ipsdmmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

Zhang

Reilly

2017

ATVB

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Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human iPSC-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this Review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing and cell therapeutics in cardiovascular diseases.

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“…Of these cell types, iPSC-derived microglia have been added to 3D cultures, showing integration, migration and maturation [131, 133]. …”

Section: Introductionmentioning

confidence: 99%

Stem cell models of Alzheimer’s disease: progress and challenges

Arber¹,

Lovejoy²,

Wray³

2017

Alz Res Therapy

116

126

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A major challenge to our understanding of the molecular mechanisms of Alzheimer’s disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in vitro studies. iPSC-neuron models have been widely employed to model AD and we discuss in this review the progress that has been made to date using patient-derived neurons to recapitulate key aspects of AD pathology and how these models have contributed to a deeper understanding of AD molecular mechanisms, as well as addressing the key challenges posed by using this technology and what progress is being made to overcome these. Finally, we highlight future directions for the use of iPSC-neurons in AD research and highlight the potential value of this technology to neurodegenerative research in the coming years.

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

Cited by 760 publications

References 79 publications

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

Stem cell models of Alzheimer’s disease: progress and challenges

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