SP 3: Bidirectional Cell Trafficking across Materno-Fetal Interfaces

Research questions, aims

This subprogram focusses on understanding the function of fetomaternal interfaces, the mechanisms involved in the bidirectional cell trafficking and the impact of extracellular vesicles. Interfaces to be evaluated will be the placenta barrier and the placenta-brain axis (blood-brain-barrier). The aim will be the identification of mechanisms of communication between fetal and maternal cells as well as of cell trafficking across the selected interfaces and functional changes caused by dysregulation of these processes.

Scientific Background

The interaction between maternal and fetal cells defines not only the outcome of the pregnancy itself but also the future wellbeing of the child, the mother, and even her additional offspring (1). The main fetomaternal interface is the placenta barrier formed by four layers of cells becoming thinner during progressing pregnancy. This dynamic reduction has functional implications for the intensity of fetomaternal transfer of substances and cells from and to the mother (2). Failure of a functional placenta barrier may be associated with pregnancy pathologies. Extracellular vesicles and soluble signals from the placenta and fetal cells can affect distant maternal organs such as brain, pancreas or heart causing “maternal programming” that may predispose to health issues. Likewise, maternal cells can cross the placenta promoting fetal immune development (3). Novel technologies are available for studying mechanisms in biological barriers in human models and will be employed in this program.

Own preceding work

We reported that placental cells secrete extracellular vesicles containing fetal-specific signals including miRNAs. These vesicles can be taken up by maternal immune cells and modify their functions (4, 5). Exogenously injected extracellular vesicles can also interact with and cross the blood-brain-barrier delivering their content to neural cells and predispose them for activation (6). In a brain-on-chip model fetal vesicles passed to maternal neural cells through modifications in the endothelium of the blood-brain-barrier. Based on our studies on ex vivo human placenta perfusion with maternal blood cells, we have proposed a bidirectional mechanism for cell trafficking across the placenta barrier (7). We aim to further investigate mechanisms and the link between vesicles and cell trafficking in biological membranes.

Method spectrum, involvement of the Medical Scientist

The Medical Scientist will use the established methods (see subprogram 1) to study fetomaternal interfaces including human ex vivo placenta perfusion and placenta- and brain-on-a-chip. Additional methods for extracellular vesicle isolation and characterization will be employed including nanotracking analysis, (glyco)proteomic technologies, and transfection of miRNAs.

Relevance for CEPRE and for Reproductive Health

Because the selected interfaces are established or modified in the first weeks of pregnancy, this subprogram will offer a link between early gestation and the persisting immunological and cerebral changes wrought by pregnancy. The Medical Scientist employed in this subprogram will contribute to understand the repercussions that fetomaternal barrier disruption will cause to the health of the mother and her offspring.

References

1. Murrieta-Coxca JM, Fuentes-Zacarias P, Ospina-Prieto S, Markert UR, Morales-Prieto DM. Synergies of Extracellular Vesicles and Microchimerism in Promoting Immunotolerance During Pregnancy. Front Immunol. 2022;13:837281.
2. Jones CJ, Harris LK, Whittingham J, Aplin JD, Mayhew TM. A re-appraisal of the morphophenotype and basal lamina coverage of cytotrophoblasts in human term placenta. Placenta. 2008;29(2):215-9.
3. Stelzer IA, Urbschat C, Schepanski S, Thiele K, Triviai I, Wieczorek A, Alawi M, Ohnezeit D, Kottlau J, Huang J, Fischer N, Mittrucker HW, Solano ME, Fehse B, Diemert A, Stahl FR, Arck PC. Vertically transferred maternal immune cells promote neonatal immunity against early life infections. Nat Commun. 2021;12(1):4706.
4. Chaiwangyen W, Murrieta-Coxca JM, Favaro RR, Photini SM, Gutierrez-Samudio RN, Schleussner E, Markert UR, Morales-Prieto DM. MiR-519d-3p in Trophoblastic Cells: Effects, Targets and Transfer to Allogeneic Immune Cells via Extracellular Vesicles. Int J Mol Sci. 2020;21(10).
5. Ospina-Prieto S, Chaiwangyen W, Herrmann J, Groten T, Schleussner E, Markert UR, Morales-Prieto DM. MicroRNA-141 is upregulated in preeclamptic placentae and regulates trophoblast invasion and intercellular communication. Transl Res. 2016;172:61-72.
6. Morales-Prieto DM, Murrieta-Coxca JM, Stojiljkovic M, Diezel C, Streicher PE, Henao-Restrepo JA, Rostel F, Lindner J, Witte OW, Weis S, Schmeer C, Marz M. Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation. Cells. 2022;11(4).
7. Murrieta-Coxca JM, Aengenheister L, Schmidt A, Markert UR, Buerki-Thurnherr T, Morales-Prieto DM. Addressing microchimerism in pregnancy by ex vivo human placenta perfusion. Placenta. 2022;117:78-86.