Endocytosis in the placenta: An undervalued mediator of placental transfer

Abstract

Endocytosis is an essential mechanism for cellular uptake in many human tissues. A range of endocytic mechanisms occur including clathrin-dependent and -independent mechanisms. However, the role of endocytosis in the placenta and the spatial localisation of individual mechanisms is not well understood.The two principal cell layers that comprise the placental barrier to maternal-fetal transfer are the syncytiotrophoblast and fetal capillary endothelium. Endocytic uptake into the syncytiotrophoblast has been demonstrated for physiological maternal molecules such as transferrin-bound iron and low density lipoprotein (LDL) and may play an important role in the uptake of several other micronutrients, serum proteins, and therapeutics at both major placental cell barriers. These mechanisms may also mediate placental uptake of some viruses and nanoparticles. This review introduces the mechanisms of cargospecific endocytosis and what is known about their localisation in the placenta, focussing predominantly on the syncytiotrophoblast. A fuller understanding of placental endocytosis is necessary to explain both fetal nutrition and the properties of the placental barrier. Characterising placental endocytic mechanisms and their regulation may allow us to identify their role in pregnancy pathologies and provide new avenues for therapeutic intervention.

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit

“…To investigate this, fresh placental villous fragments (n = 4–5 placentas per treatment) were incubated with 20 µM 25(OH)D 3 and albumin, plus the endocytic inhibitors 5 mM amiloride, 10 µM cytochalasin D, and 2 µM receptor-associated protein (RAP), which block pinocytosis, classical clathrin-dependent endocytosis, and megalin-mediated endocytosis (one type of clathrin-dependent endocytosis), respectively. The application of a range of endocytic inhibitors, which target different aspects of endocytic uptake, aimed to pinpoint the discrete machinery required for the uptake of this particular cargo ( Cooke et al, 2021 ). The vitamin D-mediated upregulation of CYP24A1 mRNA expression was significantly reduced by amiloride, cytochalasin D, and RAP in the presence of albumin ( Figure 3d , Figure 3—source data 1 ).…”

3D Visualisation of trans-syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast

“…While TSNs may form by a unique mechanism, they are more likely to co-opt at least some of the known molecular mechanisms that mediate endocytosis. There are multiple endocytic processes, including clathrin and caveolin, micropinosomes or CLIC/GEEC, which form tubular structures [23]. The CLIC/GEEC may be of particular interest as these form tube-like structures [32].…”

“…TSNs may be related to structures produced by clathrin-independent carriers (CLIC) and GPI-anchored protein-enriched early endosomal compartment (GEEC) pathways [22]. The CLIC/GEEC pathways form uncoated tubulovesicular membrane structures and identifying whether these or other molecular mechanisms underly TSN formation will be necessary for determining regulation and function [23]. It should be noted that in a 2D z slice, the TSNs can look like cytoplasmic endocytic vesicles.…”

Altered protein O-GlcNAcylation in placentas from mothers with diabetes causes aberrant endocytosis in placental trophoblast cells

“…However, here we chose clathrin-mediated endocytosis (CME) for further study. This system is crucial for micronutrient transport 35 and growth factor signalling 23 in syncytiotrophoblast, and was a high confidence hit when comparing placenta from BMI-matched mothers with tissue from T1D or T2D. We used a pull-down-Western approach to confirm that clathrin subunits and RAB proteins, all important components of the canonical endocytic machinery, are GlcNAcylated.…”