MiRNA nano-packages for maternal-placental-fetal communication

Positioned at the maternal-fetal interface, the placenta generates regulatory signals and serves as a communication junction that governs pregnancy health. In addition to hormones, growth factors and diverse proteins, we and others have recently shown that small non-coding RNA molecules, including microRNAs (miRNAs), traffic among the maternalplacental-fetal compartments, and may have a central role in maternalfetal adaptation to homeostatic perturbations. Although common and unique types of miRNAs are expressed by the placenta during pregnancy, the function of placental miRNA species remains largely unknown. We recently showed that primary human trophoblasts are resistant to infection by a heterogeneous panel of viruses, and that this resistance can be partly conferred to non-trophoblast cells by exogenous expression of trophoblast-specific miRNAs, expressed from the chromosome 19 miRNA cluster (C19MC). This effect was not observed during cell infection by nonviral placental pathogens, including Listeria monocytogenes, and Toxoplasma gondii. Trophoblastic miRNAs can be released to the extracellular space within several types of vesicles, including cell fragments, apoptotic bodies, microvesicles, and nanovesicles (exosomes), or can be packaged with non-vesicular protein complexes, such as argonaute-2. To examine the trafficking of trophoblastic miRNAs to maternal-fetal tissues we engineered a transgenic mouse that expresses a 160 kb segment of human genomic DNA harboring the human C19MC cluster. We coupled this technology with RNAseq analysis of miRNA expression in triads of placenta, maternal plasma and fetal plasma from pregnant women at term. Together, these analyses shed new light on transplacental bidirectional miRNA trafficking patterns (Supported by NIH HD06589, HD075665, HD071707, AI081759, and the Pennsylvania Department of Health Research Formula Funds)