UBC Theses and Dissertations
Characterizing ADAM28 function in trophoblast differentiation De Luca, Lauren Celeste
Human placental development is a complex process dependent on continuous cross talk between fetal and maternal uterine compartments. Trophoblasts, placental cells of fetal epithelial lineage, invade the maternal uterine lining, forming the maternal-fetal interface. This interface is vital for controlling nutrient, gas, and waste exchange between maternal and fetal circulatory systems. The differentiation of progenitor trophoblasts into highly-specific cell subsets important for placental function is a highly-regulated developmental process. Trophoblast differentiation into invasive subtypes is essential for enhancing optimal uterine artery physiology, maternal-fetal nutrient exchange, and immunotolerance in pregnancy. Trophoblast invasion is controlled by cell-cell and cell-matrix interactions, as well as through production of various growth factors, cytokines, and hormones. Insufficient trophoblast invasion results in insufficient arterial remodeling that underlies cellular events responsible for the development of pregnancy disorders such as preeclampsia and fetal growth restriction. A Disintegrin and Metalloproteinase 28 (ADAM28) is a multi-functional protein belonging to the metzincin superfamily of metalloproteinases. ADAM28 exists as two alternative splice variants: a full-length transmembrane form (ADAM28-L) and a truncated secreted variant (ADAM28-S). Recently, ADAM28 has been shown to be differentially expressed in two distinct trophoblast subtypes ex vivo; however despite this knowledge, little is known about the role of ADAM28 in placental development or trophoblast biology. My research has demonstrated that both ADAM28 isoforms are highly expressed in invasive trophoblasts of distal regions in placental columns. Utilizing a loss-of-function strategy, I demonstrate that ADAM28 promotes trophoblast column outgrowth, and directs trophoblast cell migration and survival. Collectively, these findings describe a novel role for ADAM28 in regulating the differentiation of progenitor trophoblasts into extravillous trophoblast subsets and highlight ADAM28 as a key protease in human placental development.
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