Alexander Guillermo Beristain

Placental development is a highly regulated process requiring signals from both fetal and maternal uterine compartments. Within this complex system, trophoblasts, placental cells of epithelial lineage, form the maternal-fetal interface controlling nutrient, gas and waste exchange. The commitment of progenitor villous cytotrophoblasts to differentiate into diverse trophoblast subsets is a fundamental process in placental development. Differentiation of trophoblasts into invasive stromal- and vascular- remodeling subtypes is essential for uterine arterial remodeling and placental function. Inadequate placentation, characterized by defects in trophoblast differentiation, may underlie the earliest cellular events driving pregnancy disorders such as preeclampsia and fetal growth restriction. Molecularly, invasive trophoblasts acquire characteristics defined by profound alterations in cell-cell and cell-matrix adhesion, cytoskeletal reorganization and production of proteolytic factors. A Disintegrin and Metalloproteinase 12 (ADAM12) is a multifunctional protein belonging to the ADAM family of metalloproteinases. ADAM12 exists as two alternatively spliced isoforms: ADAM12L (a transmembrane form) and ADAM12S (a truncated secreted form). ADAM12 is highly expressed in the human placenta and promotes matrix remodelling, cell proliferation and invasion in tumorigenesis. Importantly, low ADAM12 serum levels have been associated with pregnancies linked to poor pregnancy outcome. In spite of this knowledge, the importance of ADAM12 in directing trophoblast biology in early placentation is poorly understood. In this thesis, I have determined that both ADAM12 isoforms are expressed in distal ends of trophoblast columns, highly-invasive matrix-degrading trophoblasts and the invasive HTR8/SVneo trophoblastic cell line. Utilizing loss-of and gain-of-function strategies, I have demonstrated that ADAM12S plays a central role in promoting trophoblast invasion, as well as extravillous cytotrophoblast (EVT) column outgrowth through a mechanism requiring its intrinsic proteolytic activity. Moreover, I have identified cAMP signalling as the upstream regulator of ADAM12 expression and function in trophoblasts. Collectively, these findings describe a novel role for ADAM12 in directing an invasive phenotype in trophoblasts, and highlights ADAM12 as a key protease in human placental development.

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