Role of Annexine-A5 in repair and regeneration of human placenta – PlacentA5

In the human placenta, organ responsible for fetal growth and development, the multinucleated cellular layer, named syncytiotrophoblast (ST) plays a major role. Indeed ST bathing in maternal blood is the site of nutrient exchange and hormone synthesis. ST expands and regenerates all along pregnancy via the recruitment by fusion of underlying mononucleated cytotrophoblast cells. The apical membrane of ST is formed of microvilli which can brake away in the intervillous space. In addition, large ST pieces, called sprouts, are also released in the maternal blood all along pregnancy.
Preeclampsia one of the main causes of severe premature births and Intra-Uterine Growth Retardation (IUGR) are two major pregnancy pathologies from placental origin with major socio-economical and human costs. They are associated with a large release of membrane trophoblast necrotic material as well as an abnormal regeneration of the ST. These ST fragments are inflammatory for the maternal endothelial cells.
Therefore extensive membrane ruptures occur in physiological and pathological conditions, and must be compensated by efficient processes of membrane repair. Our current understanding of the mechanisms of membrane repair of the human placenta is very poor.
Recently, Partner-1 (A. Brisson) has elucidated the function of Annexin-A5 in membrane repair. Annexin-A5 discovered originally in the placenta is the prototype member of the annexins, a family of soluble proteins that share the property of binding to negatively-charged lipid membranes, principally those containing phosphatidylserine (PS) in a Ca2+-dependant manner. According to J. Rand’s hypothesis, proposed fifteen years ago, PS molecules are exposed at the ST membrane surface and Annexin-A5 forms a layer covering the ST surface, which prevents blood coagulation in the intervillous space. Despite its potential interest, this hypothesis is weakly supported by low-resolution immune-histological data.
The recent finding that Annexin-A5 occupies a central place in the machinery of membrane repair, which is of vital importance in cell’s life, constitutes a major breakthrough in Annexin-A5 research. This study concludes that Annexin-A5 promotes membrane repair via the formation of 2D arrays at the level of damaged membranes, which prevents the expansion of membrane wound and facilitates the final step of membrane resealing.
In view of 1) the role of Annexin-A5 in membrane repair, 2) the extensive membrane damages occurring at the placenta ST membrane and 3) the high Annexin-A5 content of the placenta, we postulate that Annexin-A5 is involved in membrane repair of the ST membrane.
The overall aim of the PlacentA5 project is thus to elucidate whether Annexin-A5 is involved in membrane repair of placental ST, and what is its exact role in normal and pathological placentas.
The strength of this project is the task force joining two leader teams with unique complementary expertise. Partner 1 (A. Brisson) is a leader in imaging and structure-function studies of Annexin-A5 assemblies. Partner 2 (D. Evain-Brion) is an international reference team in the field of human placenta physiology and human trophoblast differentiation, with a unique expertise in setting in vitro models of human trophoblast differentiation. This project is developed within the RTRS PremUp allowing normal and patholigical placenta collections.