Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles

Abstract

Placental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport.The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange.To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms, respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis–Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found.

The influence of placental metabolism on fatty acid transfer to the fetus

“…The maternal perfusate was recirculated for 180 min. Samples were taken from maternal artery and vein and from the fetal vein at 0, 10,20,30,60,90,120,150, and 180 min. The maternal reservoir was changed to perfusion medium containing 0.5% BSA, and both circulations were kept open during this washout phase.…”

Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation

“…A carrier-based model was used to represent the transporters, as outlined previously (22, 32). Net flux J A I → II (mol/min) of substrate A from compartment I to compartment II for the exchanger (ex) model is given by $J_{A,\mathrm{e}\mathrm{x}}^{I\to II}=V_{\mathrm{e}\mathrm{x}}\frac{{\left[A\right]}^j{\left[\mathrm{R}\right]}_{\mathrm{e}\mathrm{x}}^{II}-{\left[A\right]}^{II}{\left[\mathrm{R}\right]}_{\mathrm{e}\mathrm{x}}^L}{K_{\mathrm{e}\mathrm{x}}\left({\left[\mathrm{T}\mathrm{o}\mathrm{t}\right]}_{\mathrm{e}\mathrm{x}}^I+{\left[\mathrm{T}\mathrm{o}\mathrm{t}\right]}_{\mathrm{e}\mathrm{x}}^{II}\right)/2+{\left[\mathrm{T}\mathrm{o}\mathrm{t}\right]}_{\mathrm{B}\mathrm{x}}^I{\left[\mathrm{normalT}\mathrm{normalo}\mathrm{normalt}\right]}_{\mathrm{B}\mathrm{x}}^{II}}$ and by $J_{A,\mathrm{f}\mathrm{a}}^{I\to II}=V_{\mathrm{f}\mathrm{a}}\left(\frac{{\left[A\right]}^I}{K_{\mathrm{f}\mathrm{a}}+{\left[\mathrm{T}\mathrm{o}\mathrm{t}\right]}_{\mathrm{f}\mathrm{a}}^I}-\frac{{\left[A\right]}^{II}}{K_{\mathrm{f}\mathrm{a}}+{\left[\mathrm{normalT}\mathrm{normalo}\mathrm{normalt}\right]}_{\mathrm{f}\mathrm{a}}^{II}}\right)$…”

An international network (PlaNet) to evaluate a human placental testing platform for chemicals safety testing in pregnancy

“…It has been possible to model nutrient transfer across microvillous (apical) and basal membranes of the syncytiotrophoblast, with the knowledge of activities of transporters from microvillous and basal microvessicle experiments [65][66][67]. Likewise, eventually this should also be possible for all known drug uptake and efflux transporters present in the human placenta.…”

“…Indeed, there has been a recent surge in theoretical studies of placental morphology [91][92][93] and its relation to haemodynamics and transfer function [65,67,[94][95][96][97][98]. We now have the opportunity to combine the synergy of detailed inspection of placental barrier properties ex vivo and in vitro with the power of testing key mechanisms in silico that should accelerate the development of placenta-on-a-chip and its translation to industrial and regulatory use.…”