Abstract
Vitamin H (biotin) is delivered to the fetus transplacentally by an active biotin-transport mechanism and is critical for fetal development. Our objective was to develop a comprehensive MRI technique for mapping biotin transporter activity in the murine placenta. Visualization of transporter activity can employ MRI’s unique T2*-dependent signal ‘off-switch’, which is triggered by transporter mediated aggregation of biotinylated contrast agent (b-BSA-Gd-DTPA). MRI data were collected from pregnant mice after administration of b-BSA-Gd-DTPA and analyzed using a new sub-voxel biophysical signal model. Validation experiments included competition with native biotin, comparative tests using PET, histology, and ICPMS. MRI signal was governed by binding, aggregation, and clearance of biotin (confirmed by histology). Signal dynamics reflected the placenta’s perfusion pattern modulated by biotin transporter activity and trophoblast mediated retention, and were in congruence with a three-compartment sub-voxel model. Pre-saturation of the transporters with free biotin suppressed b-BSA-Gd-DTPA uptake. The results were confirmed by PET, histology and ICPMS. The presented MRI-based platform allows to track activity of essential molecular transporters in the placenta, reflecting a transporter-mediated uptake, followed by retention and aggregation, and recycling associated with the large b-BSA-Gd-DTPA conjugate. The presented DCE-MRI technique can furthermore be used to map and characterize microstructural compartmentation and transporter activity without exposing the fetus to contrast media.
Highlights
Biotin–Fluorescein accumulated within red blood cell (RBCs) in the blood spaces of the maternal placenta (MBS) and in the RBCs of the embryonic blood spaces (EBS) in the labyrinth (Fig. 4a–d)
The first is a demonstration that the transport of biotin to the fetus is actively mediated by placental biotin transporters resulting in biotin retention in intracellular aggregates
Our experiments revealed an active biotin uptake, retention, and clearance mechanism, as well as its spatiotemporal distribution in the placenta
Summary
The concentration of biotin in the placenta is higher than in the maternal and fetal plasma, suggesting the existence of a selective biotin-transport and retention mechanism[5,6]. This transport is mediated by N a+-dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) that is highly expressed in the human p lacenta[7]. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was used to investigate biotin transporter activity and trophoblast cell retention in the mouse placenta.
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