Placental Biophysics Workshop

29th - 30th August 2017, Frank Adams Room

Organisers: Igor Chernyavsky and Oliver Jensen.

The registration is free but mandatory for catering purposes. Please fill in the form below before Monday 31st July:

Registration Form

Directions: The meeting is held at the Alan Turing Building (map), Frank Adams Room (take a lift / stairs to the first floor and follow the signs). The closest train stations are Oxford Road and Piccadilly (15-20 min walk). The Manchester Airport is about 30 minutes taxi-ride away. Please see the University website for more information.

Programme

29th August

10:30 Coffee & Registration
11:00 Welcome
11:10 Henning Schneider (Bern) History of ex vivo dual perfusion and oxygenation of an isolated cotyledon of human placenta (Abstract)
11:55 Alys Clark (Auckland)

Placenta models to cell behaviours and back again: Can computational models improve our knowledge of the mechanisms driving placental development? (Abstract)

12:40 Lunch
13:40 Michelle Oyen (Cambridge) A microfluidics assay to study invasion of human placental trophoblast cells (Abstract)
14:25 David Elad (Tel Aviv) Tissue engineered placental barrier model for studying placental transport (Abstract)
15:10 Coffee
15:20 Bram Sengers (Southampton)        Modelling placental amino acid transfer as an integrated system (Abstract)
16:05 Philip Pearce (MIT) Image-based modelling of blood flow and oxygen transfer in feto-placental capillaries (Abstract)
16:50 Tea
17:00 Parisa Mirbod (Clarkson) Understanding blood flow and oxygen transport in the feto-placental vasculature system of the placenta from fluid dynamics point of view (Abstract)
18:30 Dinner for invited speakers

30th August

9:00 Marcel Filoche (École Polytech)  Can placental imaging data be used to validate current placental exchange models? (Abstract)
9:45 Coffee
10:00 Hans-Georg Frank (LMU München) Dynamic modelling of uteroplacental blood flow in the intervillous space: Supercomputer systems meet advanced microscopy (Abstract)
10:45 Nikhilesh Bappoo (UWA Perth)

Viscosity and haemodynamics in a late gestation rat feto-placental arterial network (Abstract)

11:30 Close & Lunch
12:30 Walk to IFPA

 

This workshop was made possible by MRC NIRG award MR/N011538/1.

 MRC logo


Abstracts

Nikhilesh Bappoo (University of Western Australia)

Viscosity and haemodynamics in a late gestation rat feto-placental arterial network

Fundamental to placental function is the development of the feto-placental arterial network. Despite the strong association of haemodynamics with vascular remodelling mechanisms, there is a lack of computational haemodynamic data to aid our understanding of feto-placental physiology. We have recently created a comprehensive 3D computational fluid dynamics model of a substructure of the rat feto-placental arterial network to investigate the influence of viscosity on wall shear stress (WSS). Late gestation rat feto-placental arteries were perfused with Microfil and scanned via micro-computed tomography to capture the vascular geometry in 3D. A detailed description of rat fetal blood viscosity parameters was developed, and three different approaches to feto-placental haemodynamics were simulated in 3D using the finite volume method: Newtonian model, non-Newtonian Carreau-Yasuda model and Fåhræus-Lindqvist effect model. Significant variability in WSS was observed between different viscosity models. The physiologically-realistic simulations using the Fåhræus-Lindqvist effect and rat fetal blood estimates of viscosity revealed detailed patterns of WSS throughout the arterial network. We found WSS gradients at bifurcation regions, which may contribute to vessel enlargement, and sprouting and pruning during angiogenesis. This simulation of feto-placental haemodynamics shows the heterogeneous WSS distribution throughout the network and demonstrates the ability to determine physiologically-relevant WSS magnitudes, patterns and gradients. This model will help advance our understanding of vascular physiology and remodelling in the feto-placental network.

Alys Clark (University of Auckland)

Placenta models to cell behaviours and back again: Can computational models improve our knowledge of the mechanisms driving placental development?

In early pregnancy, successful development of the placenta depends on maintenance of an optimal environment for villous growth and development. Trophoblast invasion into the uterine decidua promotes spiral artery remodelling to provide an increasing supply of blood to the intervillous space (IVS). At the same time, the villous structure and the placental vasculature develop within the changing environment of the IVS. Variations from normal in the rate of blood flow in the vicinity of placental cells, or the distribution of oxygenation in placental tissue can impact significantly upon the capacity of placental cells to migrate and/or proliferate. This impacts on subsequent growth and development of the placenta. Here I present a ‘top down’ approach to understanding the interaction between the placental micro-environment and cell behaviours via examples of the use of organ-level computational models of placental function to guide cell migration and proliferation assays. I then present preliminary findings from a ‘bottom up’ approach, using computational models of cell behaviours to understand the dynamic trophoblast driven changes in decidual tissue in early pregnancy.

David Elad (Tel Aviv University)

Tissue engineered placental barrier model for studying placental transport

The placenta barrier separates between maternal and fetal blood circulations and controls maternal-to-fetal transfer of oxygen and nutrients and fetal-to-maternal transfer of carbon dioxide and wastes. The mature placenta barrier is made of three layers: syncytiotrophoblasts, basal membrane and vascular endothelium. Accordingly, we developed a tissue engineered placental barrier model by constructing a multi-layer co-culture of endothelial cells (i.e., HUVEC) and trophoblast cells (i.e., HTR8) on both sides of a denuded amniotic membrane. For this purpose we developed a custom-designed well, composed of a cylindrical medium holder and a well bottom. The well-bottom with the co-cultured cells was installed in a two-compartment flow chamber that can hold 3 well bottoms. Each chamber was connected in series with a controled peristaltic pump that drived culture medium through the compartments to mimic maternal and fetal capillary blood flows on both sides of the placental barrier. We studied maternal-to-fetal glucose transport and the flavonoid quercetin. Presently we develop a more standard co-culture model for regulation protocols using a collagen coated synthetic PTFE porous membrane.

Marcel Filoche (École Polytechnique)

Can placental imaging data be used to validate current placental exchange models?

Several studies since 1960-s have demonstrated that the overall efficiency of the placenta as an exchanger cannot be evaluated by only considering the scale of individual exchange units (villi), without taking the large-scale placental structure into account. Recent computational and theoretical developments in this field have identified important structural factors defining the exchange rate. However, these predictions lack solid experimental validation, which slows down further progress. In this talk, we will present recent results of our group that try to bridge the gap between theory and experiment. We have developed an automatic image analysis algorithm allowing us to determine the exact positions, areas and perimeters of more than 17,000 villi per placenta (as well as fetal capillaries in each of them) from routine H&E stained placental microphotographs. The proposed method not only provides much greater accuracy for the traditionally measured characteristics averaged over the whole placenta and allows one to study their regional variations, but also gives access to quantitative distributions of sizes, areas and perimeters of the villi, IVS and fetal capillaries inside the given placenta. We will then present the results of application of the method to 22 healthy, 2 diabetic and 1 pre-eclamptic placenta with IUGR, and discuss their interpretation within our earlier developed stream-tube placenta model (STPM).

Hans-Georg Frank (Ludwig Maximilian University of Munich)

Dynamic modelling of uteroplacental blood flow in the intervillous space: Supercomputer systems meet advanced microscopy

Insufficient remodelling of uterine spiral arteries is an early pregnancy event which is linked to intrauterine growth retardation and preeclampsia. However, its impact on the micro-rheology in the intervillous space (IVS) cannot be examined clinically and rheological animal models of the human IVS do not exist. Thus, an in silico approach could potentially shed light on the micro-rheology which is inaccessible in vivo.
Here, we report
- on the advanced 3D reconstruction of an entire inflow region of a spiral artery from serial histological sections. The spiral artery was found still attached to the basal plate of a placenta of a patient with IUGR after birth;
- on spatially highly resolved dynamic flow modelling inside the morphological frame provided by the 3D reconstructions of an arterial inflow region, and
- on validation of our finding of elevated shear stress at the villous surface by a modelling-guided morphological approach. We provided evidence of elevated trophoblast shedding in IUGR placentas at the villous surface.
The example of our study shows that detailed morphological work combined with high-end computing resources can assist in identifying micro-rheology-associated pathology in the placenta.
[1] Roth CJ, Haeussner E, Ruebelmann T, Edler von Koch F, Schmitz C, Frank HG, Wall WA (2017) Sci Rep 7: 40771.

Parisa Mirbod (Clarkson University)

Understanding blood flow and oxygen transport in the feto-placental vasculature system of the placenta from fluid dynamics point of view

The placenta is a transient vascular organ that enables nutrients and blood gases to be exchanged between fetal and maternal circulations. To understand how mass transfers between the fetus and mother, we must analyze the structure of the placental vasculature from large vessels to the small capillary vessels that contribute to gas and nutrient exchange. In this study, we present steps made to understand and model the detailed structure and oxygen transfer between the fetal and maternal red blood cells in the feto-placental vasculature system in human placenta. A model was proposed from a fluid dynamics point of view by accounting for a number of ‘conductive’ symmetrical branches and a minimal resistance path to maximize blood flow to the terminal villi, which are the sites where high resistance oxygen diffusion occurs. It was then predicted that the most efficient fetal oxygen transport through the vasculature system is provided by a flow structure consist of 17 bifurcation levels in the human placenta. This model can be used to predict parameters, such as volume flow rate and the feto-placental capillary diameter, pressure drop in the vasculature system, which enables computation of these specific parameters in the placenta that are difficult to measure experimentally. Wherever possible, we compared model predictions with experimental results reported in the literature and found good agreement between the experimental measurements and theoretical predictions.

Michelle Oyen (University of Cambridge)

A microfluidics assay to study invasion of human placental trophoblast cells

Pre-eclampsia, fetal growth restriction and stillbirth are major pregnancy disorders throughout the world. The underlying pathogenesis of these diseases is defective placentation characterised by inadequate invasion of extravillous placental trophoblast cells into the uterine arteries. How trophoblast invasion is controlled remains an unanswered question. Here, we describe an in vitro microfluidic invasion assay to study the migration of primary human trophoblast cells. Each experiment can be performed with a small number of cells making it possible to conduct research on human samples despite the challenges of isolating primary trophoblast cells. Cells embedded in a three-dimensional (3D) hydrogel microenvironment are exposed to a chemical gradient in the microfluidic device. Cell motion at the individual cell level is tracked in 3D using real-time high-resolution imaging, so that dynamic readouts on cell migration such as directionality, motility and velocity are obtained. The microfluidic system was validated using isolated trophoblast and a gradient of granulocyte-macrophage colony-stimulating factor, a cytokine produced by activated decidual Natural Killer cells. This microfluidic model provides detailed analysis of the dynamics of trophoblast migration compared to previous assays and can be modified in future to study in vitro how human trophoblast behaves during placentation.

Philip Pearce (Massachusetts Institute of Technology)

Image-based modelling of blood flow and oxygen transfer in feto-placental capillaries

A multi-scale model of the human placenta will require the simulation of blood flow and oxygen transfer in large feto-placental capillary networks. In the first part of this work, the aim is to understand oxygen transfer in single fetal capillaries. To this end, three-dimensional representations of villous and capillary surfaces, obtained from confocal laser scanning microscopy, are converted to finite-element meshes. Simulations of blood flow and oxygen transfer are performed to calculate the vascular flow resistance of the capillaries and the total oxygen transfer rate from the maternal blood. Scaling arguments, which predict the oxygen transfer across a range of flow rates, are shown to be an efficient tool for quantifying the effect of structural variability. In the second part of the work, a method for extending the derived scaling laws to capillary networks is presented, allowing the effects of network structure and hematocrit on fetal oxygen supply to be quantified.

Henning Schneider (University of Bern)

History of ex vivo dual perfusion and oxygenation of an isolated cotyledon of human placenta

The history of ex vivo dual perfusion of an isolated cotyledon of human placenta started in the sixties of the last century in Paris. At the “Unité de Recherche sur la Physiologie du Placenta” Professor Maurice Panigel together with his group had described a preparation of separate ex vivo circuits of the fetal and the corresponding segment of maternal compartment in a single cotyledon. For the perfusion of the villous vascutature an arterial branch together with the vein were cannulated on the chorionic plate. For the perfusion of the maternal segment, on the decidual surface the remnant of a dilated spiral artery was cannulated. Radioangiography pictures of the two ex vivo circuits in the isolated cotyledon of the human placenta were quite similar to what Elizabeth Ramsey had published for the whole placenta in the rhesus monkey in vivo [1, 2].
In October 1968, I started working as a research assistant with Prof. Panigel. I tried to simplify the technique and instead of cannulation of a spiral artery I tested access to the intervillous space by directly penetrating the decidual plate. In the summer of 1969 Prof. Joseph Dancis from New York University Medical School spend a sabbatical in the lab of Prof. Panigel and together with him we showed using this modification, that preferential transport of the carrier mediated L-Leucine from the maternal to the fetal compartment was functional. The maintenance of energy dependant membrane transport systems for L-amino acids under rather unphysiological conditions was quite convincing. We later confirmed this with additional experiments in the research lab of Joe Dancis at New York. This adaptation of the dual ex vivo perfusion of an isolated human placental cotyledon was first published in 1972 in the American Journal of Obstetrics and Gynecology [3]. This publication received worldwide attention and the method is being used by an ever increasing number of different groups.
[1] Panigel M, Pascaud M, Brun JL (1967) J Physiol (Paris) 59: 277.
[2] Ramsey EM, et al. (1967) Am J Obstet Gynecol 98: 419-423.
[3] Schneider H, Panigel M, Dancis J (1972) Am J Obstet Gynecol 114: 822-828.

Bram Sengers (University of Southampton)

Modelling placental amino acid transfer as an integrated system

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.

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