Computational modelling of amino acid transfer interactions in the placenta

Abstract

Placental amino acid transport is essential for fetal development during pregnancy. Impaired transport has been associated with restricted fetal growth that can potentially lead to diseases in later life. However, quantitative understanding of placenta transport remains limited and therefore requires investigation. The aim of this study was to develop a computational framework that can represent the amino acid transport system in the placenta as a whole.

The transfer of amino acid across the placenta is mediated by a broad array of specific membrane transporters. Mathematical models, based on carrier-mediated transport theory, were developed to mechanistically represent these transporters. These include accumulative transporters, which use secondary active transport driven by the sodium electrochemical potential; exchangers (antiporters), which swap one substrate for another on different sides of the membrane; and facilitative transporters, which transport substrate along its concentration gradient. The transporter models were thoroughly investigated and validated with experimental data with respect to their mechanistic characteristics and parameter sensitivity. Overall, the models were demonstrated to be adequate in representing the specific transporter behaviours.There are 20 amino acids, including 9 essential ones, and over 19 different transporters, all of which act on certain overlapping subsets of these amino acids. All transporters must work interdependently for successful transfer of the required amino acids from the maternal to the fetal side; however, this complex process is not fully understood. A compartmental model of placental amino acid transport incorporating kinetic transporter models was developed and revealed to be able to sufficiently capture the integrated transport system. Modelling results clearly demonstrated how modulating specific transporter activity can increase the transport of certain classes of amino acids, but that this comes at the price of decreasing the transport of others, which could have potential implications for developing new clinical treatment options. This integrated modelling approach along with kinetic models of transporters will help in gaining an improved quantitative understanding of epithelial transport in the placenta and other systems and it is ultimately hoped that this will contribute to the development of clinical applications to intervene or prevent impaired-transport related pathologies.

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Identifiers

ORCID for Bram Sengers: orcid.org/0000-0001-5859-6984

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