Membrane-type MMPs are indispensable for placental labyrinth formation and development

Abstract

IntroductionAfter embryo implantation and decidualization, a critical step in placental development is the formation of the placental labyrinth (LA), which enables nutrient and gas exchange between the embryonic vasculature and the maternal blood supply. 1-5 LA formation is associated with substantial tissue remodeling and cell differentiation, as well as ingrowth of the embryonic vasculature through the chorion to a point of immediate proximity with the maternal blood supply. During this process, chorionic trophoblasts (CHs) differentiate into 2 perivascular cell populations that form distinct bilaminar envelopes of syncytiotrophoblasts in immediate contact with the fetal vascular endothelium. 6 Multiple transcription factors, growth factors, adhesion molecules, and gap junction molecules are known to influence the formation of the LA. 7 Interestingly, few if any proteolytic enzymes have so far been proven essential for LA formation although tissue remodeling is considered an integral part of this morphogenetic process. Several of the matrix metalloproteinases (MMPs), cathepsins, and serine proteinases are expressed in the placenta during development, however to date none have proven indispensable for development of the LA and in turn development of the embryo to term. [8][9][10][11][12] Among the 6 known membrane-type MMP (MT-MMP) molecules in the mouse, MT1-MMP and MT3-MMP possess pericellular collagenase activity and are required for both prenatal and postnatal remodeling of the major fibrillar collagen types, cell surface receptors, and signaling molecules. [13][14][15] Ablation of MT1-MMP deprives cells of the ability to migrate through and process several both permanent and provisional extracellular matrices, and in vivo leads to severe defects in postnatal remodeling of connective tissues. [16][17][18][19] Moreover, MT1-MMP is required in the stromal compartment for efficient dissemination of malignant epithelial cells in mouse mammary carcinoma. 20 MT1-MMP deficiency is partially mitigated by the activity of the molecular relative, MT3-MMP, which shares at least some overlapping substrate specificity with MT1-MMP. Accordingly, incremental loss of alleles encoding each molecule markedly exacerbates the cellular matrix remodeling deficit in a gene dosage dependent manner, and double deficiency results in severe developmental deficits and perinatal death, but importantly, not preterm loss of embryos. 15 As expected from these observations, MT1-MMP and MT3-MMP are frequently coexpressed in the same tissue compartments. The placental LA however is devoid of MT3-MMP expression but displays conspicuous expression of another MT-MMP family member, MT2-MMP. 11,21 So far, the function of MT2-MMP has been determined biochemically and in cell-based assays. Under these conditions, MT2-MMP displays the ability to process basement membrane components and fibrillar collagen matrices whereas its role in vivo has remained unexplored. 22,23 Here we demonstrate that MT2-MMP deficiency in the mouse is compatible with develop...

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development

“…Results such as ours are often countered by the argument that the mouse genome encodes more than 20 MMP family members, but virtually all of these genes have now been targeted and, with the exception of Mmp14, each knockout gives rise to viable mice with normal lifespans (Bonnans et al, 2014;Holmbeck et al, 1999;Itoh, 2015;Rowe and Weiss, 2009;Zhou et al, 2000). The fact that only Mmp14 targeting causes a dramatic increase in the morbidity and mortality of knockout mice (Holmbeck et al, 1999;Zhou et al, 2000) and that dual targeting of Mmp14 and Mmp15 results in an embryonic lethal phenotype (Szabova et al, 2010) have, predictably, catalyzed increased efforts to identify the key functions of these proteinases. Clearly, MMP14 and MMP15 do exert complex effects on mammary gland development, but the observed changes in function are, for the most part, novel and unanticipated from the perspective of current paradigms.…”

“…As Mmp14/Mmp15 double-null mice die during embryogenesis (Szabova et al, 2010), we alternatively targeted both proteinases selectively in the mammary epithelial compartment, but these analyses demonstrated that branching morphogenesis nevertheless proceeds in a normal fashion from birth through adulthood (our unpublished observations). Interestingly, a double-knockout system was recently employed to target Mmp14 and Mmp15 in postnatal mice wherein mammary gland involution was unaffected (Szabova et al, 2010), suggesting that adult mammary tissue remodeling likewise proceeds in a MT-MMP-independent fashion. Although MMP14 and MMP15 have previously been shown to endow neoplastic cells with the ability to degrade basement membrane (BM) barriers (Ota et al, 2009), it should be stressed that there is no evidence that mammary epithelial cells dissolve their underlying BM during morphogenesis in vivo.…”

Relaxin Enhances the Collagenolytic Activity and In Vitro Invasiveness by Upregulating Matrix Metalloproteinases in Human Thyroid Carcinoma Cells

“…As shown previously, MT1-MMP and MMP2 were present in fetal trophoblast cells of human placenta used as positive control (data not shown; ref. 48). …”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…The fetal portion of the placenta, in particular the labyrinth (LA), displays strong overlapping expression of MT1-MMP and MT2-MMP, which is critical for syncytiotrophoblast formation and for fetal vessels. Both MT1-MMP and MT2-MMP are crucial specifically during development of LA, showing a selective temporal and spatial MMP activity required for the development of the mouse embryo (Szabova et al, 2010). The trophoblast compartment of the placenta comprises various subpopulations with distinct functions.…”