Computational modelling of placental amino acid transfer as an integrated system

N Panitchob,K.L Widdows,I.P Crocker,E.D Johnstone,C.P Please,C.P Sibley,J.D Glazier,R.M Lewis,B.G Sengers

doi:10.1016/j.bbamem.2016.03.028

Abstract

Placental amino acid transfer is essential for fetal development and its impairment is associated with poor fetal growth. Amino acid transfer is mediated by a broad array of specific plasma membrane transporters with overlapping substrate specificity. However, it is not fully understood how these different transporters work together to mediate net flux across the placenta. Therefore the aim of this study was to develop a new computational model to describe how human placental amino acid transfer functions as an integrated system. Amino acid transfer from mother to fetus requires transport across the two plasma membranes of the placental syncytiotrophoblast, each of which contains a distinct complement of transporter proteins. A compartmental modelling approach was combined with a carrier based modelling framework to represent the kinetics of the individual accumulative, exchange and facilitative classes of transporters on each plasma membrane. The model successfully captured the principal features of transplacental transfer. Modelling results clearly demonstrate how modulating transporter activity and conditions such as phenylketonuria, can increase the transfer of certain groups of amino acids, but that this comes at the cost of decreasing the transfer of others, which has implications for developing clinical treatment options in the placenta and other transporting epithelia.

Highlights

The placenta is the interface between the maternal and fetal circulations and plays an essential role in mediating the transfer of all the nutrients required for fetal development, including amino acids
Impaired placental transfer of amino acids during pregnancy is associated with poor fetal growth, which increases the risk of poor pregnancy outcomes such as stillbirth [1] and of chronic disease in adult life [2,3,4]
This section will first explore how amino acids are transferred to the fetus across each syncytiotrophoblast plasma membrane (MVM and basal plasma membrane (BM)) separately

Summary

Introduction

The placenta is the interface between the maternal and fetal circulations and plays an essential role in mediating the transfer of all the nutrients required for fetal development, including amino acids. Transfer of amino acids across the placenta is a complex process, influenced by multiple factors including placental blood flow, membrane transporters, intracellular metabolism and placental morphology [5,6]. Order to pass from the maternal intervillous space into the fetal capillaries, amino acids need to cross the placental syncytiotrophoblast, an epithelial barrier separating the two circulations. Amino acids in the maternal blood first need to be transported across the microvillous plasma membrane (MVM) of the placental syncytiotrophoblast into the cytosol. They can either undergo metabolism or can be transported across the fetalfacing basal plasma membrane (BM), from where it is assumed they diffuse across the fetal capillary endothelium to the fetal circulation [6]

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Conclusion