Vincent Center for Reproductive Biology, Massachusetts General Hospital, 55 Fruit Street, Thier Research Building, 903B, Boston, MA, 02114, USA.
Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
J Neuroinflammation. 2024 Jun 25;21(1):163. doi: 10.1186/s12974-024-03157-w.
The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is 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.
We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). 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 (HBC-iMGs), with 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.
SARS-CoV-2 病毒激活母体和胎盘免疫反应。在怀孕期间其他感染的情况下，这种激活已知会影响胎儿大脑发育。母体免疫激活对神经发育的影响至少部分是通过胎儿大脑小胶质细胞介导的。然而，小胶质细胞无法进行直接分析，也没有经过验证的非侵入性替代模型来评估宫内小胶质细胞的启动和功能。我们之前已经证明了在小鼠模型中，小胶质细胞和 Hofbauer 细胞（HBC，即胎儿胎盘巨噬细胞）之间存在共享的转录程序。
我们评估了母体 SARS-CoV-2 对从 24 个足月胎盘分离的 HBC 的影响（N=10 例 SARS-CoV-2 阳性病例，14 例阴性对照）。使用单细胞 RNA 测序，我们证明了 HBC 亚群表现出不同的细胞程序，其中特定的亚群受到 SARS-CoV-2 的不同影响。差异表达基因的评估暗示了某些亚群中吞噬作用受损，这是 HBC 和小胶质细胞的关键功能之一。利用先前验证的小胶质细胞突触修剪模型，我们表明，从 SARS-CoV-2 阳性妊娠胎盘分离的 HBC 可以被转分化为小胶质细胞样细胞（HBC-iMGs），与阴性对照的 HBC 模型相比，其突触修剪行为受损。
这些发现表明，出生时分离的 HBC 可用于创建后代小胶质细胞编程的个性化细胞模型。
