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Projekt
Mast cells as critical regulators of tissue remodeling during implantation and placentation: mechanisms of action and mediators
Antragstellerin
Professorin Dr. Ana Claudia Zenclussen
Fachliche Zuordnung
Dermatologie
Förderung
Förderung von 2009 bis 2019
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 124661816
Mast cells (MCs) are largely known as primary responders in allergic reactions and important cells of the innate immune system. We have recently showed that besides these well-characterized functions, MCs emerge as critical modulators of embryo implantation and thereby decisively influence fetal growth and development. MC-deficient KitW-sh/W-sh mice present a clear phenotype of impaired implantation, which can be rescued by previous reconstitution with bone marrow-derived mast cells (BMMCs). MCs positively influence tissue remodeling necessary for implantation of the blastocysts via TGF-β/CtGF interplay. We also demonstrated that MCs produce and secrete galectin-1 (Gal-1), which is of importance for placentation as reconstitution of MC-deficient animals with Gal-1 knockout MCs results in late pregnancy loss as results of impaired placentation and inadequate spiral artery remodeling. Here, we aim to understand how and most importantly through which mediators and cellular interactions MCs influence first, tissue remodeling necessary for nidation and implantation and second, formation of spiral arteries and placentation. The main aims of the present project are 1) to isolate and characterize uterine MCs as they seem to be different from other MCs, 2) to investigate how the absence of MCs or the deficiency of putative mediators in MCs, such as Gal-1, affect uterine blood flow, formation of spiral arteries and placentation, 3) to unravel whether and how MCs interact with uterine NK cells to ensure correct spiral artery formation and thereby placentation as these two cell types seem to have similar, redundant functions by the same mediators and 4) to address whether placentation and pregnancy can be achieved in mice lacking both, uterine MCs and uterine NKs. We do believe that our study will contribute to the knowledge of the basic mechanisms regulating embryo implantation, placentation and pregnancy maintenance and to bring to light a further role for MCs as disease modulators.
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