A Microphysiological Model to Mimic the Placental Remodeling during Early Stage of Pregnancy under Hypoxia-Induced Trophoblast Invasion.

Placental trophoblast invasion is critical for establishing the maternal-fetal interface, yet the mechanisms driving trophoblast-induced maternal arterial remodeling remain elusive. To address this gap, we developed a three-dimensional microfluidic placenta-on-chip model that mimics early pregnancy placentation in a hypoxic environment. By studying human umbilical vein endothelial cells (HUVECs) under oxygen-deprived conditions upon trophoblast invasion, we observed significant HUVEC artery remodeling, suggesting the critical role of hypoxia in placentation. In particular, we found that trophoblasts secrete matrix metalloproteinase (MMP) proteins under hypoxic conditions, which contribute to arterial remodeling by the degradation of extracellular matrix components. This MMP-mediated remodeling is critical for facilitating trophoblast invasion and proper establishment of the maternal-fetal interface. In addition, our platform allows real-time monitoring of HUVEC vessel contraction during trophoblast interaction, providing valuable insights into the dynamic interplay between trophoblasts and maternal vasculature. Collectively, our findings highlight the importance of MMP-mediated arterial remodeling in placental development and underscore the potential of our platform to study pregnancy-related complications and evaluate therapeutic interventions.

MNSFß regulates placental development by conjugating IGF2BP2 to enhance trophoblast cell invasiveness.

OBJECTIVES: Success in pregnancy in mammals predominantly depends on a well-developed placenta. The differentiation of invasive trophoblasts is a fundamental process of placentation, the abnormalities of which are tightly associated with pregnancy disorders including preeclampsia (PE). Monoclonal nonspecific suppressor factor beta (MNSFß) is an immunosuppressive factor. Its conventional knockout in mice induced embryonic lethality, whereas the underlying mechanism of MNSFß in regulating placentation and pregnancy maintenance remains to be elucidated. METHODS: Trophoblast-specific knockout of MNSFß was generated using Cyp19-Cre mice. In situ hybridization (ISH), haematoxylin and eosin (HE), immunohistochemistry (IHC) and immunofluorescence (IF) were performed to examine the distribution of MNSFß and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at the foeto-maternal interface. The interaction and expression of MNSFß, IGF2BP2 and invasion-related molecules were detected by immunoprecipitation (IP), immunoblotting and quantitative real-time polymerase chain reaction (qRT-PCR). The cell invasion ability was measured by the Transwell insert assay. RESULTS: We found that deficiency of MNSFß in trophoblasts led to embryonic growth retardation by mid-gestation and subsequent foetal loss, primarily shown as apparently limited trophoblast invasion. In vitro experiments in human trophoblasts demonstrated that the conjugation of MNSFß with IGF2BP2 and thus the stabilization of IGF2BP2 essentially mediated the invasion-promoting effect of MNSFß. In the placentas from MNSFß-deficient mice and severe preeclamptic (PE) patients, downregulation of MNSFß was evidently associated with the repressed IGF2BP2 expression. CONCLUSIONS: The findings reveal the crucial role of MNSFß in governing the trophoblast invasion and therefore foetal development, and add novel hints to reveal the placental pathology of PE.

Hypoxia and Placental Development.

Hemochorial placentation is orchestrated through highly regulated temporal and spatial decisions governing the fate of trophoblast stem/progenitor cells. Trophoblast cell acquisition of specializations facilitating invasion and uterine spiral artery remodeling is a labile process, sensitive to the environment, and represents a process that is vulnerable to dysmorphogenesis in pathologic states. Hypoxia is a signal guiding placental development, and molecular mechanisms directing cellular adaptations to low oxygen tension are integral to trophoblast cell differentiation and placentation. Hypoxia can also be used as an experimental tool to investigate regulatory processes controlling hemochorial placentation. These developmental processes are conserved in mouse, rat, and human placentation. Consequently, elements of these developmental events can be modeled and hypotheses tested in trophoblast stem cells and in genetically manipulated rodents. Hypoxia is also a consequence of a failed placenta, yielding pathologies that can adversely affect maternal adjustments to pregnancy, fetal health, and susceptibility to adult disease. The capacity of the placenta for adaptation to environmental challenges highlights the importance of its plasticity in safeguarding a healthy pregnancy. Birth Defects Research 109:1309-1329, 2017.© 2017 Wiley Periodicals, Inc.