Cells Transferred from Parent to Fetus are Important for Brain Development
Post by Lani Cupo
The takeaway
During development in the womb, some maternal cells are transferred to the fetus, seeding fetal organs, including the brain. These cells, known as maternal microchimeric cells (MMc), are shown to persist until adulthood, playing a key role in establishing homeostasis and preventing excessive synaptic pruning.
What's the science?
MMc have previously been discovered in mammalian pregnancy, however, it is unclear whether they contributed functionally to brain development or merely represented a leak of cells through the placenta. This week in Nature Communications, Schepanski and colleagues investigate the function of MMc in a mouse model of pregnancy, establishing the importance of these cells for microglia homeostasis, brain wiring, and early behavioral development.
How did they do it?
The authors examined mouse offspring at three timepoints: at gestational day (GD) 18.5 (the end of pregnancy, roughly equivalent to the end of the second trimester of human pregnancy), postnatal day (PND) 8, and PND 60 (early adulthood). The authors’ comprehensive approach can be broken down into three stages: 1) identify and characterize MMc in development, 2) explore the purpose of MMc by reducing the number in a mouse model, and 3) restore MMc in this model to confirm the effect.
1) First, the authors searched for the presence of MMc at each timepoint and used a cell-identification technique known as flow cytometry to examine the location and identity of MMc in the brain. To further explore cellular diversity among MMc, the authors used single-cell RNA-sequencing to cluster the cells into nine different groups, and then identify the cell types based on what genes each group differentially expresses.
2) After the initial characterization, the authors created a genetic mouse line with reduced MMc to test the impact on offspring. They examined a) the number of immune cells in both groups (MMcLow, a group with fewer MMc, and MmcPos, the control group), reporting results at GD 18.5 and PND 8. They also examined b) gene expression with RNA-sequencing, c) the concentration of glutamatergic synapses, indicating short- and long-range projection neurons, d) electrical activity in the prelimbic area of the prefrontal cortex (PL) and hippocampus, and e) behavioral differences between offspring groups.
3) Finally, the authors create another model where they re-introduce MMc to developing fetuses from the strain that have fewer MMc in an attempt to reverse the effects, which would provide strong evidence that the differences they see are truly due to the lack of MMc.
What did they find?
1) First, the authors found MMc declined with age but were still present in early adulthood (PND 60). The majority of MMc were comprised of immune cells, including T and B cells and microglia. These cells were present largely in the prefrontal cortex and hippocampus, as well as other brain regions such as the cerebellum and limbic areas. Of the nine clusters, 5 comprised microglia, and the remaining groups were T, B, endothelial, and neuron-like cells.
2) Comparing the MMcLow and MmcPos groups, the authors found at GD 18.5, more microglia but fewer T and B cells in the MMcLow group than in the MmcPos group, although these differences resolved at PND 8. Additionally, the authors found differentially expressed genes suggesting a hyperactive immune system in the MMcLow group. Examining the glutamatergic projection neurons, the authors found fewer synapses in the MMcLow group, indicating fewer short and long-range projections. In terms of electrical activity in the PL and hippocampus, the authors report reduced activity in the MMcLow group, as well as weakened coupling between the prefrontal cortex and hippocampus, implicating this circuit. Finally, in terms of behavior, the authors found changes in ultrasonic calls pups make when separated from their dams, potentially indicating emotional distress in the MMcLow group compared to MmcPos. They also report a difference in recognition memory, with MMcLow pups exploring novel objects less than controls, an important behavior for early development.
3) In the rescue group, where MMc were introduced with adoptive transfer to an MMcLow group, none of the findings differed between MMcLow and the control group.
What's the impact?
This extensive study establishes the role of MMc in the developing brain, showing that they are important in promoting microglia homeostasis, brain wiring, and behavioral performance. This study could provide a framework for future research to develop early biomarkers of neurodevelopmental disorders.