Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function

Takata, Kazuyuki; Kozaki, Tatsuya; Lee, Christopher Zhe Wei; Thion, Morgane Sonia; Otsuka, Masayuki; Lim, Shawn; Utami, Kagistia Hana; Fidan, Kerem; Park, Dong Shin; Malleret, Benoît; Chakarov, Svetoslav; See, Peter; Low, Donovan; Low, Gillian; Garcia-Miralles, Marta; Zeng, Ruizhu; Zhang, Jinqiu; Goh, Chi Ching; Gül, Ahmet; Hubert, Sandra; Lee, Bernett; Chen, Jinmiao; Low, Ivy; Shadan, Nurhidaya Binte; Lum, Josephine; Wei, Tay Seok; Mok, Esther; Kawanishi, Shohei; Kitamura, Yoshihisa; Larbi, Anis; Rénia, Laurent; Ng, Lai Guan; Wolf, Yochai; Önder, Tamer T.; Newell, Evan W.; Huber, Tara L.; Ashihara, Eishi; Garel, Sonia; Pouladi, Mahmoud A.; Ginhoux, Florent

doi:10.1016/j.immuni.2020.01.004

Cited by 37 publications

(72 citation statements)

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“…17 Insights into the existence of selfrenewing tissue-resident myeloid cells were mainly provided by studies in mice models, [18][19][20] with evidence in humans being still scarce. 21 Human monocytes are classified into 3 major subsets according to their differential expression of CD14 and CD16: classical CD14 11 CD16 2 , intermediate CD14 11 CD16 1 , and nonclassical CD14 1 CD16 11 monocytes. 22 Further, other surface markers such as Slan/ M-DC8 proved useful to distinguish classical vs intermediate/ nonclassical monocytes.…”

Section: Introductionmentioning

confidence: 99%

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

et al. 2018

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Classical CD16− vs intermediate/nonclassical CD16+ monocytes differ in their homing potential and biological functions, but whether they differentiate into dendritic cells (DCs) with distinct contributions to immunity against bacterial/viral pathogens remains poorly investigated. Here, we employed a systems biology approach to identify clinically relevant differences between CD16+ and CD16− monocyte-derived DCs (MDDCs). Although both CD16+ and CD16− MDDCs acquire classical immature/mature DC markers in vitro, genome-wide transcriptional profiling revealed unique molecular signatures for CD16+ MDDCs, including adhesion molecules (ITGAE/CD103), transcription factors (TCF7L2/TCF4), and enzymes (ALDH1A2/RALDH2), whereas CD16− MDDCs exhibit a CDH1/E-cadherin+ phenotype. Of note, lipopolysaccharides (LPS) upregulated distinct transcripts in CD16+ (eg, CCL8, SIGLEC1, MIR4439, SCIN, interleukin [IL]-7R, PLTP, tumor necrosis factor [TNF]) and CD16− MDDCs (eg, MMP10, MMP1, TGM2, IL-1A, TNFRSF11A, lysosomal-associated membrane protein 1, MMP8). Also, unique sets of HIV-modulated genes were identified in the 2 subsets. Further gene set enrichment analysis identified canonical pathways that pointed to “inflammation” as the major feature of CD16+ MDDCs at immature stage and on LPS/HIV exposure. Finally, functional validations and meta-analysis comparing the transcriptome of monocyte and MDDC subsets revealed that CD16+ vs CD16− monocytes preserved their superior ability to produce TNF-α and CCL22, as well as other sets of transcripts (eg, TCF4), during differentiation into DC. These results provide evidence that monocyte subsets are transcriptionally imprinted/programmed with specific differentiation fates, with intermediate/nonclassical CD16+ monocytes being precursors for pro-inflammatory CD103+RALDH2+TCF4+ DCs that may play key roles in mucosal immunity homeostasis/pathogenesis. Thus, alterations in the CD16+/CD16− monocyte ratios during pathological conditions may dramatically influence the quality of MDDC-mediated immunity.

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Section: Introductionmentioning

confidence: 99%

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

et al. 2018

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“…Additionally, the morphological complexity of the brain macrophages, which is an indicator of microglial branching (ramified form), in the Ts1Cje embryos seemed to be lower in comparison to WT controls and Ts1Cje‐Erg +/+/Mld2 mice (Figure C). Thus, a morphological analysis, taking into account cell circularity analysis, was performed as previously published . This revealed that Ts1Cje brain macrophages were more circular than those in WT mice, whereas the circularity of Ts1Cje‐Erg +/+/Mld2 brain macrophages was closer to that of WT mice (Figure D).…”

Section: Resultsmentioning

confidence: 70%

Perturbation of the immune cells and prenatal neurogenesis by the triplication of the Erg gene in mouse models of Down syndrome

et al. 2019

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Some mouse models of Down syndrome (DS), including Ts1Cje mice, exhibit impaired prenatal neurogenesis with yet unknown molecular mechanism. To gain insights into the impaired neurogenesis, a transcriptomic and flow cytometry analysis of E14.5 Ts1Cje embryo brain was performed. Our analysis revealed that the neutrophil and monocyte ratios in the CD45-positive hematopoietic cells were relatively increased, in agreement with the altered expression of inflammation/immune-related genes, in Ts1Cje embryonic brain, whereas the relative number of brain macrophages was decreased in comparison to wild-type mice. Similar upregulation of inflammationassociated mRNAs was observed in other DS mouse models, with variable trisomic region lengths. We used genetic manipulation to assess the contribution of Erg, a trisomic gene in these DS models, known to regulation hemato-immune cells. The perturbed proportions of immune cells in Ts1Cje mouse brain were restored in Ts1Cje-Erg +/+/Mld2 mice, which are disomic for functional Erg but otherwise trisomic on a Ts1Cje background. Moreover, the embryonic neurogenesis defects observed in Ts1Cje cortex were reduced in Ts1Cje-Erg +/+/Mld2 embryos. Our findings suggest that Erg gene triplication contributes to the dysregulation of the homeostatic proportion of the populations of immune cells in the embryonic brain and decreased prenatal cortical neurogenesis in the prenatal brain with DS.Brain Pathology 30 (2020) 75-91Brain Pathology 30 (2020) 75-91

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“…Even more importantly, functional analyses of human microglia are still lacking and are urgently required. Since the first protocols for generating microglia from iPSCs were reported just 3 years ago [86][87][88], human iPSC-derived microglia have become a gold standard for in vitro studies of microglia-mediated mechanisms of diseases [89,90]. Importantly, microglial-like cells are present in organoids, opening the door to study human microglia in a complex environment that recapitulates the living brain [91].…”

Section: Are Human Microglia Similar To Microglia From Animal Models?mentioning

confidence: 99%

Cien Años de Microglía: Milestones in a Century of Microglial Research

Sierra

Paolicelli

Kettenmann

2019

Trends in Neurosciences

141

127

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The year 2019 marks the 100-year anniversary of the discovery of microglia by Pío del Río-Hortega. We will recount the state of neuroscience research at the beginning of the 20th century and the heated scientific dispute regarding microglial identity. We will then walk through some of the milestones of microglial research in the decades since then. In the last 20 years, the field has grown exponentially. Researchers have shown that microglia are unlike any other resident macrophages: they have a unique origin and distinguishing features. Microglia are extraordinarily motile cells and constantly survey their environment, interacting with neurons, astrocytes, oligodendrocytes, neural stem cells, and infiltrating immune cells. We finally highlight some open questions for future research regarding microglia's identity, population dynamics, and dual (beneficial and detrimental) role in pathology.

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Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function

Cited by 37 publications

References 0 publications

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

Perturbation of the immune cells and prenatal neurogenesis by the triplication of the Erg gene in mouse models of Down syndrome

Cien Años de Microglía: Milestones in a Century of Microglial Research

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