Human fetal microglia acquire homeostatic immune-sensing properties early in development

Kracht, Laura; Borggrewe, Malte; Eskandar, Sharon; Brouwer, Nieske; Lopes, Susana M. Chuva de Sousa; Laman, Jon D.; Scherjon, Sicco A.; Prins, Jelmer R.; Kooistra, Susanne M.; Eggen, Bart J. L.

doi:10.1126/science.aba5906

Cited by 112 publications

(128 citation statements)

References 58 publications

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“…Human microglia have not been extensively studied at the embryonic level; however, studies by Zhong et al and Kracht et al corroborate mouse data, suggesting there is a higher level of heterogeneity in the gestational period, which culminates in microglia acquiring a more homeostatic phenotype (76,77). Like mice, human microglia can be differentiated based on their developmental stage, suggesting there is a progressive developmental program for human microglia development.…”

Section: Similarities Between Human and Murine Microgliamentioning

confidence: 95%

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Microglia Diversity in Health and Multiple Sclerosis

et al. 2020

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Multiple Sclerosis (MS) is a neurodegenerative disease characterized by multiple focal lesions, ongoing demyelination and, for most people, a lack of remyelination. MS lesions are enriched with monocyte-derived macrophages and brain-resident microglia that, together, are likely responsible for much of the immune-mediated neurotoxicity. However, microglia and macrophage also have documented neuroprotective and regenerative roles, suggesting a potential diversity in their functions. Linked with microglial functional diversity, they take on diverse phenotypes developmentally, regionally and across disease conditions. Advances in technologies such as single-cell RNA sequencing and mass cytometry of immune cells has led to dramatic developments in understanding the phenotypic changes of microglia and macrophages. This review highlights the origins of microglia, their heterogeneity throughout normal ageing and their contribution to pathology and repair, with a specific focus on autoimmunity and MS. As phenotype dictates function, the emerging heterogeneity of microglia and macrophage populations in MS offers new insights into the potential immune mechanisms that result in inflammation and regeneration.

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Section: Similarities Between Human and Murine Microgliamentioning

confidence: 95%

“…Functions have yet to be ascribed to these phenotypes, but initial steps have been taken to compare microglia clusters to functions based on gene ontology designations (77).…”

Section: Similarities Between Human and Murine Microgliamentioning

confidence: 99%

Microglia Diversity in Health and Multiple Sclerosis

et al. 2020

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“…As QC thresholds we choose to adopt a 3 × Mean Absolute Deviation (MAD) range for outlier cut-off, as reported previously ( Kracht et al., 2020 ). We determined outliers across four parameters: nCount_RNA, nFeature_RNA, percent.mt, percent.rb.…”

Section: Methodsmentioning

confidence: 99%

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

et al. 2021

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Summary The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD.

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“…9f-g). Unique to the developing testes, we find a new population of macrophages expressing genes characteristic of microglia (CX3CR1, P2RY12, C3, OLFML3, HTRA1, TREM2) 63,65,66 that we named fetal microglia-like cells (Fig. 6b-d; Supplementary Fig.…”

Section: Crosstalk Between Germ and Supporting Cells Shapes Ovarian Architecturementioning

confidence: 99%

Single-cell roadmap of human gonadal development

Vento‐Tormo¹,

García-Alonso²,

Lorenzi³

et al. 2021

Preprint

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Gonadal development is a complex process that involves sex determination followed by divergent maturation into ovaries or testes. Historically, limited tissue accessibility and lack of reliable in vitro models have impeded our understanding of human gonadogenesis, despite its importance in gonadal pathologies and infertility. Here, we generated a comprehensive map of first- and second-trimester gonadal development using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and imaging. Using this approach, we identified novel transcription factors and cell states in human germ and supporting cell lineages. We compared them with other mammalian species and found primate-specific regulatory programmes. Our data identified cell context–specific interactions shaping sex specification and development of human germ cells. We defined a novel bipotent progenitor cell (LGR5+, TSPAN8+) in late embryos that can differentiate into early Sertoli in males or pre-granulosa cells in females. In fetal ovaries, we defined two subsets of pre-granulosa cells supporting germ-cell differentiation and distributed across the cortico-medullary axis. We also found a subset of developing granulosa cells appearing during the second trimester of pregnancy that is involved in follicular assembly. In fetal testes, we defined a novel supporting population (sPAX8 cells) located at the poles of the developing testis cords. We also found two tissue-resident myeloid populations that we named microglia-like and SIGLEC15+ fetal testicular macrophages. This study provides an unprecedented spatiotemporal map of human gonadal differentiation that can be utilised as a blueprint for in vitro gametogenesis.

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Human fetal microglia acquire homeostatic immune-sensing properties early in development

Cited by 112 publications

References 58 publications

Microglia Diversity in Health and Multiple Sclerosis

Microglia Diversity in Health and Multiple Sclerosis

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

Single-cell roadmap of human gonadal development

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