Engineered models for placental toxicology: Emerging approaches based on tissue decellularization.

Recent increases in prescriptions and illegal drug use as well as exposure to environmental contaminants during pregnancy have highlighted the critical importance of placental toxicology in understanding and identifying risks to both mother and fetus. Although advantageous for basic science, current in vitro models often fail to capture the complexity of placental response, likely due to their inability to recreate and monitor aspects of the microenvironment including physical properties, mechanical forces and stiffness, protein composition, cell-cell interactions, soluble and physicochemical factors, and other exogenous cues. Tissue engineering holds great promise in addressing these challenges and provides an avenue to better understand basic biology, effects of toxic compounds and potential therapeutics.

Disease-specific extracellular matrix composition regulates placental trophoblast fusion efficiency.

The placental syncytiotrophoblast is a multinucleated layer that regulates transport between the mother and fetus. Fusion of trophoblasts is essential to form this layer, but this process can be disrupted in pregnancy-related disorders such as preeclampsia. Disease progression is also associated with changes in the extracellular matrix (ECM), but whether disease-specific ECM compositions play any causal role in establishing syncytiotrophoblast disease phenotypes remains unknown.

The implications of the purinergic signaling throughout pregnancy.

Purinergic signaling is a necessary mechanism to trigger or even amplify cell communication. Its ligands, notably adenosine triphosphate (ATP) and adenosine, modulate specific membrane-bound receptors in virtually all human cells. Regardless of the stage of the pregnancy, cellular communication between maternal, placental, and fetal cells is the paramount mechanism to sustain its optimal status.

Mechanobiological regulation of placental trophoblast fusion and function through extracellular matrix rigidity.

The syncytiotrophoblast is a multinucleated layer that plays a critical role in regulating functions of the human placenta during pregnancy. Maintaining the syncytiotrophoblast layer relies on ongoing fusion of mononuclear cytotrophoblasts throughout pregnancy, and errors in this fusion process are associated with complications such as preeclampsia. While biochemical factors are known to drive fusion, the role of disease-specific extracellular biophysical cues remains undefined.

Biomimetic Micropatterned Adhesive Surfaces To Mechanobiologically Regulate Placental Trophoblast Fusion.

The placental syncytiotrophoblast is a giant multinucleated cell that forms a tree-like structure and regulates transport between mother and baby during development. It is maintained throughout pregnancy by continuous fusion of trophoblast cells, and disruptions in fusion are associated with considerable adverse health effects including diseases such as preeclampsia. Developing predictive control over cell fusion in culture models is hence of critical importance in placental drug discovery and transport studies, but this can currently be only partially achieved with biochemical factors.

An insight into the role of the death receptor CD95 throughout pregnancy: Guardian, facilitator, or foe.

The prototype death receptor CD95 (Fas) and its ligand, CD95L (FasL), have been thoroughly studied due to their role in immune homeostasis and elimination of infected and transformed cells. The fact that CD95 is present in female reproductive cells and modulated during embryogenesis and pregnancy has raised interest in its role in immune tolerance to the fetoplacental unit. CD95 has been shown to be critical for proper embryonic formation and survival.

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells.

Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor pathways. Hypoxia/reoxygenation (H/R) induces oxidative damage and apoptosis. These consequences activate autophagy, which degrades damaged cellular content, as well as activates Nrf2 the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, and thereby the expression of protective genes.

Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation.

Melatonin has been proposed as a possible treatment for the deleterious effects of hypoxia/reoxygenation (H/R), such as autophagy, inflammation, and apoptosis. Pathological pregnancies, such as preeclampsia, are associated with placental H/R, and decreased placental melatonin synthesis as well as lower melatonin levels in the placenta and maternal plasma. However, the effects of exogenous melatonin on inflammation and autophagy induced by pregnancy complications associated with H/R await investigation.

Testosterone replacement maintains smooth muscle content in the corpus cavernosum of orchiectomized rats.

Objective: To evaluate the effects of testosterone (T) on the maintenance of corpus cavernosum (CC) structure and apoptosis.

Methods: Animals were divided into three groups: sham operation group ( = 8) underwent sham operation; Orchiectomized (Orchiec)+ oily vehicle group ( = 8) underwent bilateral orchiectomy and received a single dose of oily vehicle by intramuscular injection (i.m.

In Vitro Induction of Hypoxia/Reoxygenation on Placental Cells: A Suitable Model for Understanding Placental Diseases.

Lack of blood flow and aberrant levels of oxygenation in placentas are recurrent in pregnancy diseases, such as preeclampsia. These alterations generate situations of hypoxia and hypoxia/reoxygenation (H/R) and consequent oxidative stress, increased cell death, and inflammation in trophoblasts. The models used to understand the effects of hypoxia and H/R on trophoblasts require a rather big structure.

Human Primary Trophoblast Cell Culture Model to Study the Protective Effects of Melatonin Against Hypoxia/reoxygenation-induced Disruption.

This protocol describes how villous cytotrophoblast cells are isolated from placentas at term by successive enzymatic digestions, followed by density centrifugation, media gradient isolation and immunomagnetic purification. As observed in vivo, mononucleated villous cytotrophoblast cells in primary culture differentiate into multinucleated syncytiotrophoblast cells after 72 hr. Compared to normoxia (8% O2), villous cytotrophoblast cells that undergo hypoxia/reoxygenation (0.

Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders.

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus.

Direct contact with particulate matter increases oxidative stress in different brain structures.

Introduction: Several experimental and epidemiological studies have demonstrated the neurological adverse effects caused by exposure to air pollution, specifically in relation to pollutant particulate matter (PM). The objective of this study was to investigate the direct effect of PM in increased concentrations in different brain regions, as well as the mechanisms involving its neurotoxicity, by evaluating oxidative stress parameters in vitro.

Methods: Olfactory bulb, cerebral cortex, striatum, hippocampus and cerebellum of rats were homogenized and incubated with PM < 2.

Placental melatonin system is present throughout pregnancy and regulates villous trophoblast differentiation.

Melatonin is highly produced in the placenta where it protects against molecular damage and cellular dysfunction arising from hypoxia/re-oxygenation-induced oxidative stress as observed in primary cultures of syncytiotrophoblast. However, little is known about melatonin and its receptors in the human placenta throughout pregnancy and their role in villous trophoblast development. The purpose of this study was to determine melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), and melatonin receptors (MT1 and MT2) expression throughout pregnancy as well as the role of melatonin and its receptors in villous trophoblast syncytialization.