Go with the Flow-Trophoblasts in Flow Culture

Abstract

With establishment of uteroplacental blood flow, the perfused fetal chorionic tissue has to deal with fluid shear stress that is produced by hemodynamic forces across different trophoblast subtypes. Amongst many other cell types, trophoblasts are able to sense fluid shear stress through mechanotransduction. Failure in the adaption of trophoblasts to fluid shear stress is suggested to contribute to pregnancy disorders. Thus, in the past twenty years, a significant body of work has been devoted to human- and animal-derived trophoblast culture under microfluidic conditions, using a rather broad range of different fluid shear stress values as well as various different flow systems, ranging from commercially 2D to customized 3D flow culture systems. The great variations in the experimental setup reflect the general heterogeneity in blood flow through different segments of the uteroplacental circulation. While fluid shear stress is moderate in invaded uterine spiral arteries, it drastically declines after entrance of the maternal blood into the wide cavity of the intervillous space. Here, we provide an overview of the increasing body of evidence that substantiates an important influence of maternal blood flow on several aspects of trophoblast physiology, including cellular turnover and differentiation, trophoblast metabolism, as well as endocrine activity, and motility. Future trends in trophoblast flow culture will incorporate the physiological low oxygen conditions in human placental tissue and pulsatile blood flow in the experimental setup. Investigation of trophoblast mechanotransduction and development of mechanosome modulators will be another intriguing future direction.

Keywords: development; flow culture; placenta; pregnancy; trophoblast.

Figure 1

Potential route of maternal blood flow into the intervillous space during first trimester. During early placental development, maternal blood flow in maternal uterine spiral arteries is obstructed by extravillous trophoblast plugs. However, parts of maternal blood (red arrows) can pass through narrow intertrophoblastic gaps when trophoblast plugs begin to dissolve during first trimester of gestation. The laminar blood flow from the maternal spiral artery changes to a turbulent flow upon entrance into the intervillous space.

Figure 2

Influence of fluidic flow on different trophoblast subtypes. Fluidic flow regulates differentiation and physiology of both, the syncytiotrophoblast (STB) and extravillous trophoblasts (EVTs). During syncytialization, cell-cell contact proteins, such as desmoplakin and E-cadherin are downregulated, and the structural protein ezrin relocalizes from the basal to the apical side. Formation and appearance of microvilli on the apical surface as well as accumulation of lipid droplets in the STB are influenced by fluidic flow. Moreover, fluidic flow affects expression and localization of GLUT1, secretion of hCG as well as conversion of cortisol to cortisone. In the EVT subpopulation, formation of filopodia, and hence migratory behavior is regulated by fluidic flow as well.