Gatekeepers of the fetus: Characterization of placental macrophages

Megli, Christina; Coyne, Carolyn B.

doi:10.1084/jem.20202071

Cited by 13 publications

(7 citation statements)

References 10 publications

(14 reference statements)

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“…Transplacental transmission of virus capable of infecting neural tissue can have lasting and devastating consequences on the developing fetal brain. A key factor in understanding potential fetal infection risk is whether maternally acquired SARS-CoV-2 can transmit across the placenta, the primary physiological and immunological barrier preventing viral transmission from the maternal to fetal circulation [116][117][118]. The preponderance of evidence to date suggests that adverse neurodevelopmental effects of SARS-CoV-2 infection, at least with the ancestral strain and strains preceding the B.1.617.2 (Delta) variant, are more likely to occur via maternal and placental immune activation and downstream impact on the developing fetal brain, rather than via direct fetal infection with SARS-CoV-2 in utero [28,119].…”

Section: Transplacental Transmission Of Sars-cov-2 and Direct Fetal I...mentioning

confidence: 99%

“…More recently, these protocols have been adapted to generate microglia-like cells from umbilical cord blood [162], providing a more direct means of characterizing the impact of in utero exposures for a specific individual. Another emerging strategy utilizes Hofbauer cells, fetal placental macrophages which may be isolated from the placenta after delivery and cultured [116]. An advantage of these cells is that, like microglia, they are yolk sac-derived, and thus may closely mimic the exposures and developmental processes of brain microglia [163].…”

Section: The Role Of Cellular Models In Understanding Mechanisms Of R...mentioning

confidence: 99%

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COVID-19 in pregnancy: implications for fetal brain development

Shook

Sullivan

et al. 2022

Trends in Molecular Medicine

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The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on the developing fetal brain is poorly understood. Other antenatal infections such as influenza have been associated with adverse neurodevelopmental outcomes in offspring. Although vertical transmission has been rarely observed in SARS-CoV-2 to date, given the potential for profound maternal immune activation, impact on the developing fetal brain is likely. Here we review evidence that SARS-CoV-2 and other viral infections during pregnancy can result in maternal, placental and fetal immune activation, and ultimately in offspring neurodevelopmental morbidity. Finally, we highlight the need for cellular models of fetal brain development to better understand potential short- and long-term impacts of maternal SARS-CoV-2 infection on the next generation.

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Section: Transplacental Transmission Of Sars-cov-2 and Direct Fetal I...mentioning

confidence: 99%

Section: The Role Of Cellular Models In Understanding Mechanisms Of R...mentioning

confidence: 99%

COVID-19 in pregnancy: implications for fetal brain development

Shook

Sullivan

et al. 2022

Trends in Molecular Medicine

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“…Male fetal origin was confirmed by high expression of DDX3Y and low expression of XIST in 8 subclusters; these were labeled HBC 0-7 (Figure 1B). The macrophage cluster with high expression of XIST (consistent with maternal origin) was annotated as placenta-associated maternal macrophages and monocytes (PAMMs, Figure 1B) (27). A small cluster of monocytes – identified as such by high expression of monocyte marker genes S100A8 , S100A9 , and TIMP1 – demonstrated equal expression levels of both DDX3Y and XIST , suggesting that both fetal and maternal cells were present in this monocyte cluster.…”

Section: Resultsmentioning

confidence: 99%

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

Shook,

Batorsky,

De Guzman

et al. 2023

Preprint

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The SARS-CoV-2 virus activates maternal and placental immune responses, which in the setting of other infections occurring during pregnancy are known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Here, we assessed the impact of maternal SARS-CoV-2 on HBCs isolated from term placentas using single-cell RNA-sequencing. We demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells, with altered morphology and impaired synaptic pruning behavior compared to HBC models from negative controls. These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

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“…Despite their recognized importance in immune signaling at the maternal-fetal interface (Reyes and Golos, 2018), Hofbauer cells remain under-characterized due to challenges in cell isolation and maintenance of viability (Megli and Coyne, 2020). Thus, while microglia have been demonstrated to be a highly heterogeneous cell type with subsets of cells performing specialized functions (Hammond et al, 2019;Kracht et al, 2020), there is a relative lack of knowledge regarding Hofbauer cell subsets and their functions.…”

Section: Discussionmentioning

confidence: 99%

Single cell profiling of Hofbauer cells and fetal brain microglia reveals shared programs and functions

Ceasrine

Batorsky

Shook

et al. 2021

Preprint

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SummaryMaternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many of which are mediated by in utero microglial programming. Microglia remain inaccessible at birth and throughout development, thus identification of noninvasive biomarkers that can reflect fetal brain microglial programming may permit screening and intervention during critical developmental windows. Here we used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells). Single-cell RNA sequencing of murine fetal brain and placental macrophages demonstrated shared transcriptional programs. Comparison with human datasets demonstrated that placental resident macrophage signatures are highly conserved between mice and humans. Single-cell RNA-seq identified sex differences in fetal microglial and Hofbauer cell programs, and robust differences between placenta-associated maternal macrophage/monocyte (PAMM) populations in the context of a male versus a female fetus. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, potentially facilitating the early identification of offspring most vulnerable to neurodevelopmental disorders.

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Gatekeepers of the fetus: Characterization of placental macrophages

Cited by 13 publications

References 10 publications

COVID-19 in pregnancy: implications for fetal brain development

COVID-19 in pregnancy: implications for fetal brain development

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

Single cell profiling of Hofbauer cells and fetal brain microglia reveals shared programs and functions

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