FM Emmi Lokka defended the dissertation in Medical Microbiology and Immunology entitled “Foetal monocytes and their journey from liver to periphery: PLVAP marks the exit” at the University of Turku on 24 October 2023 at 12.00 (University of Turku, Dentalia, Arje Scheinin lecture hall, Lemminkäisenkatu 2, Turku).

Opponent: Professor Steffen Jung (Weizmann Institute of Science, Israel)
Custos: Docent Pia Rantakari (University of Turku)

Doctoral Dissertation at UTUPub: https://urn.fi/URN:ISBN:978-951-29-9480-9

ABSTRACT

Endothelium is the barrier between the blood and tissue stroma. Cells and macromolecules are selectively allowed to traffic through the endothelium to maintain homeostasis. Besides the paracellular transport route at the cell-cell junctions, transcellular pathways also exist. Fenestrae, transendothelial channels, and caveolae are specific structures of endothelial cells. They may be covered by a filtering unit called diaphragm, which is a proteinaceous structure that consists only of plasmalemma vesicle associated protein (PLVAP). PLVAP is known to participate in molecular sieving and cellular transmigration through the endothelium. Nevertheless, the role of PLVAP in the transendothelial cell migration has not been described during the foetal era.
The aims of this thesis were to study if PLVAP is functional in leukocyte trafficking in the foetal liver and to examine the dynamics of PLVAP expression in the liver sinusoidal endothelium. We found that PLVAP was needed for the efficient exit of foetal macrophage precursors from the liver to the bloodstream. Moreover, we discovered that the resident macrophage populations in adult mice were diminished under PLVAP deficiency. Surprisingly, we also observed nondiaphragmal PLVAP expression in the sinusoids of postnatal liver that persisted until adulthood. Finally, we aimed to study the resident macrophage ontogeny in depth in testis, which is known to accommodate a substantial macrophage population. Using the PLVAP-deficient mice and other models we revealed that testicular macrophages are mostly derived from foetal origins and that circulating monocytes in the adult mice have a negligible contribution to them. Furthermore, we showed that the resident macrophages in foetal testis are crucial for the normal spermatogenesis in mice.

These results are encouraging for further investigation of PLVAP functionalities in the context of general transendothelial leukocyte migration, but also for studying the functions of PLVAP outside diaphragms. Equally intriguing will be to further examine the functions of macrophages needed in the foetal testis to support normal tissue function.

KEYWORDS: Tissue development, tissue-resident macrophage, monocytes, testis, liver sinusoidal endothelium, haematopoiesis, PLVAP, transmigration