Microchimeric Cells: (Trans-oral) Routes to and Presence in the Host

Thomas Kroneis, Gottfried Schatz Research Center, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Austria

Supervisor:	PD Dr. Thomas Kroneis
Availability:	This position is available.
Offered by:	Medical University of Graz
Application deadline:	Applications are accepted between August 03, 2022 00:00 and September 20, 2022 23:59 (Europe/Zurich)

Background:

During pregnancy, some cells manage to traffic from the fetus into the mother and vice versa giving rise to microchimerism (MC) – a phenomenon in which an individual hosts a small number of cells originating from another (genetically different) individual. In humans this microchimeric cells can persist beyond pregnancy thereby founding the basis for a lifelong MC. Microchimeric cells can differentiate into almost any cell type in the host, and implant in almost any tissue type. The consensus is that MC plays a paradoxical role in host health: some studies show benefits, others suggest it may play a role in the development of diseases. MC has been proposed to play a role in maternal wound healing, but may also be associated with pregnancy complications, such as pre-eclampsia and spontaneous abortion, as well as cancer and auto-immune diseases. MC may also play a role in providing immunological protection for the developing fetus, but also has been associated with offspring autoimmune disorders. Both, the routes of the microchimeric cells into the host and the biological meaning in the host are still unclear and lack a theory unifying its paradoxical effects.

We launched a John Templeton Foundation-funded project on microchimerism connecting experts in evolutionary medicine, reproductive immunology, biochermistry, and single-cell analysis to address basic scientific questions in microchimerism research including short-term and long-term fetal and maternal microchimerism with a special focus on immunology.

We recently developed methods unambiguously identifying haplo-identical cells (i.e., maternal and fetal) allowing to assess the frequency of microchimeric cells in host tissues and are currently developing approaches towards spatial histology using in situ techniques to characterize tissues at the single cell level. Combination of these techniques will be a focus in the ongoing projects to identify microchimeric cells, their biological function and their microenvironment.

 

Hypothesis and Objectives:

Trans-oral route into the host: Maternal cells with stem cell potential transmigrate into the amniotic fluid and are swallowed by the fetus. From the fetal digestive tract, the microchimeric cells transmigrate into fetal tissues. The project tests if (1) maternal cells are present in amniotic fluids and (2) if these cells have stem-cell properties. In addition, the project will (3) screen fetal organs, especially fetal intestine for the presence of maternal cells.

 

Methodology:

In the project the candidate will use histological (e.g., tissue pre-analytics, sectioning, staining), molecular biology techniques (ddPCR, qPCR, FISH, in situ techniques) and conventional and cell culture (e.g., differentiation assays) to identify and characterize cells.

 

References:

Bianchi, D.W., Khosrotehrani, K., Way, S.S., MacKenzie, T.C., Bajema, I., O’Donoghue, K., 2021. Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism. Clin. Chem. 67, 351–362. https://doi.org/10.1093/clinchem/hvaa304

Boddy, A.M., Fortunato, A., Wilson Sayres, M., Aktipis, A., 2015. Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb. BioEssays 37, 1106–1118. https://doi.org/10.1002/bies.201500059

De Coppi, P., Bartsch, G., Siddiqui, M.M., Xu, T., Santos, C.C., Perin, L., Mostoslavsky, G., Serre, A.C., Snyder, E.Y., Yoo, J.J., Furth, M.E., Soker, S., Atala, A., 2007. Isolation of amniotic stem cell lines with potential for therapy. Nat. Biotechnol. 25, 100–106. https://doi.org/10.1038/nbt1274

Drabbels, J.J.M., van de Keur, C., Kemps, B.M., Mulder, A., Scherjon, S.A., Claas, F.H.J., Eikmans, M., 2011. HLA-targeted flow cytometric sorting of blood cells allows separation of pure and viable microchimeric cell populations. Blood 118, e149–e155. https://doi.org/10.1182/blood-2011-06-362053

Hofmann, L., Kroneis, T., El-Heliebi, A., 2020. Using In Situ Padlock Probe Technology to Detect mRNA Splice Variants in Tumor Cells. Methods Mol. Biol. Clifton NJ 2148, 361–378. https://doi.org/10.1007/978-1-0716-0623-0_23

Kroneis, T., Geigl, J.B., El-Heliebi, A., Auer, M., Ulz, P., Schwarzbraun, T., Dohr, G., Sedlmayr, P., 2011. Combined Molecular Genetic and Cytogenetic Analysis from Single Cells after Isothermal Whole-Genome Amplification. Clin Chem 57, 1032–41. https://doi.org/10.1373/clinchem.2011.162131

Mold, J.E., Michaelsson, J., Burt, T.D., Muench, M.O., Beckerman, K.P., Busch, M.P., Lee, T.-H., Nixon, D.F., McCune, J.M., 2008. Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero. Science 322, 1562–1565. https://doi.org/10.1126/science.1164511

Nelson, J.L., 2012. The otherness of self: microchimerism in health and disease. Trends Immunol. 33, 421–427. https://doi.org/10.1016/j.it.2012.03.002

Seppanen, E., Fisk, N.M., Khosrotehrani, K., 2013. Pregnancy-acquired fetal progenitor cells. J. Reprod. Immunol. 97, 27–35. https://doi.org/10.1016/j.jri.2012.08.004

Srivatsa, B., Srivatsa, S., Johnson, K.L., Samura, O., Lee, S.L., Bianchi, D.W., 2001. Microchimerism of presumed fetal origin in thyroid specimens from women: a case-control study. The Lancet 358, 2034–2038. https://doi.org/10.1016/S0140-6736(01)07099-4

Ståhlberg, A., El-Heliebi, A., Sedlmayr, P., Kroneis, T., 2017. Unravelling the biological secrets of microchimerism by single-cell analysis. Brief. Funct. Genomics. https://doi.org/10.1093/bfgp/elx027