Abstract
During first trimester pregnancy, trophoblast cells invade from the placenta into the maternal decidua where they anchor the placenta and remodel luminal structures like spiral arteries. This process depends on proteases secreted by invading trophoblasts, which degrade extracellular matrix (ECM). We here aimed to identify proteases particularly important for trophoblast invasion. We generated a list of proteases capable of degrading decidual ECM and trophoblast integrins using MEROPS database and compared expression of these proteases between primary trophoblasts isolated from first trimester placenta (FT, n = 3), representing an invasive phenotype, vs trophoblasts isolated from term pregnancy (TT, n = 3), representing a non-invasive trophoblast phenotype. Matrix metalloproteinase 12 (MMP12) revealed highest expression levels in FT, with absent expression in TT. In situ hybridisation and immunofluorescence localised MMP12 specifically to extravillous trophoblasts (evCT) whilst Ki67 co-staining revealed that proliferating trophoblasts of the cell columns were almost negative for MMP12. Quantification revealed a decline in MMP12 positive evCT at the end of first trimester, when oxygen levels start rising. MMP12 promoter analysis identified potential binding sites for hypoxia-inducible factor (HIF-1) and other oxygen-sensitive transcription factors. Moreover, MMP12 protein was increased by low oxygen in FT in vitro and by addition of a HIF-1α activator. Collectively, MMP12 is a highly expressed protease specific for invasive evCT during the first trimester. MMP12 down regulation by increasing oxygen concentration enables temporal expression control of MMP12 and involves several mechanisms including HIF-1α. These findings suggest MMP12 involved in trophoblast invasion during the first trimester.
Highlights
During the first trimester of pregnancy, a specific subset of placental trophoblasts differentiate into invasive, extravillous cytotrophoblasts and invade into the maternal decidua
Besides matrix metalloproteinases (MMPs), other proteases contribute to extracellular matrix (ECM) degradation or to integrin shedding to eventually facilitate trophoblast invasion, such as members of the ADAMs family (Pollheimer et al 2014)
Using MEROPS database, we identified 53 human proteases involved in cleavage of these substrates, of which 46 were measured by the microarray (Online Resource 1). 24 of these proteases were expressed in first trimester placenta (FT) with 12 of them being higher expressed in FT than in noninvasive term placenta (TT)
Summary
During the first trimester of pregnancy, a specific subset of placental trophoblasts differentiate into invasive, extravillous cytotrophoblasts (evCT) and invade into the maternal decidua. Along their invasion pathway, evCT form compact cell columns that anchor the placenta to the uterine wall. Matrix metalloproteinases (MMPs) are a family of key proteinases involved in ECM degradation, and various MMPs including MMP2, 9, 7 and 14 were implicated in trophoblast invasion in vitro and in vivo (reviewed by (Cohen et al 2006)). Besides MMPs, other proteases contribute to ECM degradation or to integrin shedding to eventually facilitate trophoblast invasion, such as members of the ADAMs (a disintegrin and metalloproteinase) family (Pollheimer et al 2014)
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