No abstract

The transplacental passage of thyroid hormones from the maternal circulation to the fetal circulation within the human hemochorial placenta is important for normal fetal development, particularly the development of the central nervous system. The role of maternal thyroid hormones is particularly important in the first half of pregnancy, before the onset of endogenous thyroid hormone production in the fetus. The human placenta regulates the quantity and composition of different forms of transported thyroid hormones to ensure that the requisite levels are present in the fetus for each stage of development. Transplacental thyroid hormone supply to the fetus is modulated by several factors, including the following proteins: plasma membrane transporters, which regulate the passage of thyroid hormones in and out of cells; iodothyronine deiodinases, which metabolize thyroid hormones; and proteins within trophoblast cells, which bind thyroid hormones. In pathological situations of either maternal or fetal thyroid hormone deficiency during pregnancy, the placenta seems to lack the full compensatory mechanisms necessary to optimize maternal-fetal transfer of thyroid hormones. Inadequate passage of thyroid hormones can lead to suboptimal fetal thyroid hormone levels, which might contribute to the neurodevelopmental delay associated with such conditions. Thus, maintaining normal maternal thyroid hormone status is likely to be the primary factor in ensuring adequate transplacental thyroid hormone passage and appropriate iodide supply to the fetus.

These data support a role for vitamin D in EVT invasion during human placentation and suggest that vitamin D-deficiency may contribute to impaired EVT invasion and pre-eclampsia.

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin β4 regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin β4 improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin β4 in the kidney is unknown. We demonstrate that thymosin β4 is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin β4 did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin β4 in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin β4 in the migration of these cells. Thymosin β4 knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin β4 is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression.

The transplacental passage of thyroid hormones (THs) from mother to fetus in humans has been deduced from observational clinical studies and is important for normal fetoplacental development. To investigate the transporters that regulate TH uptake by syncytiotrophoblast (the primary barrier to maternal-fetal exchange, which lies in direct contact with maternal blood), we isolated the microvillous plasma membrane (MVM) of human term syncytiotrophoblasts. We have demonstrated that MVM vesicles express plasma membrane TH transporter proteins, including system-L (L-type amino acid transporter 1 and CD98), monocarboxylate transporters (MCTs) 8 and 10, organic anion-transporting polypeptides 1A2 and 4A1. We provide the first definitive evidence that the human syncytiotrophoblast MVM is capable of rapid, saturable T4 and T3 uptake at similar rates and in a Na+-independent manner. These two major forms of THs could not significantly inhibit each others' uptake, suggesting that each is mediated by largely different transporters. No single transporter was noted to play a dominant role in either T4 or T3 uptake. Using combinations of transporter inhibitors that had an additive effect on TH uptake, we provide evidence that 67% of saturable T4 uptake is facilitated by system-L and MCT10 with a minor role played by organic anion-transporting polypeptides, whereas 87% of saturable T3 uptake is mediated by MCT8 and MCT10. Our data demonstrate that syncytiotrophoblast may control the quantity and forms of THs taken up by the human placenta. Thus, syncytiotrophoblast could be critical in regulating transplacental TH supply from the mother to the fetus.