Placenta Magazine English

placenta

(noun [C]; plural: placentas or placentae)

The temporary organ that feeds a fetus (= developing baby) inside its mother's womb

PLACENTA MAGAZINE 2023

AUTHOR Michelle Broekhuizen m.broekhuizen@erasmusmc.nl

COVER ILLUSTRATION

Vijselaar en Sixma

LAYOUT Studio Amy Guijt

PRINT Groenprint.nl

Copyright © 2023 Michelle Broekhuizen. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, by photocopying, recording, or otherwise, without prior written permission of the author. Financial support by the Rotterdams vrouwenfonds for the publication of this magazine is gratefully acknowledged.

PREFACE

Probably you never thought about this, but it is thanks to a good function of your own placenta that you are now able to read this magazine. At the very beginning of our lives, our placenta was the first organ that was formed from the clump of cells from which we also originated. The placenta connected us to our mother, facilitating the exchange of nutrients, gasses and waste products. It was thus very important for our development.

A while after we were born, our placenta was also born. With the exception of a minority of people – perhaps your placenta has been buried, or processed into pill form, or art – the placenta is usually thrown straight into the trash bin. However, the placenta offers chances. Until this day, we still know very little about this organ, while we do know that diseases during pregnancy can be caused by an insufficient function of the placenta, that can affect the development of the child.

During my PhD I studied how the placenta changes in diseases during pregnancy, with the ultimate goal to improve the health of the (unborn) child by finding treatment opportunities for pregnancy disorders.

In this magazine I share my most important findings with you.

Michelle Broekhuizen

WASTE

Dr. Sinno Simons – Neonatologist, Erasmus MC

WASTE MATERIAL, THAT IS HOW WE CALL URINE, BLOOD, AND OTHER LEFT-OVER FLUIDS AND MATERIALS FROM MEDICAL TREATMENTS IN SCIENCE. INSTEAD OF THROWING IT AWAY, WE PREFER TO USE THESE MATERIALS FOR RESEARCH, OF COURSE WITH CONSENT OF THE PATIENT, BECAUSE IT IS STILL ‘PATIENT MATERIAL’.

It also fits into the sustainability goals. In a time where we drink latte with oat milk and gas prizes have never been higher, even hospitals are going green. Where computer used to be switched on 24/7, they are now switched off more often, and nowadays we drink coffee from a cardboard cup with a bamboo stirring rod. So why would we throw something away that we can still learn from? It seems an open door…

The placenta used to be, and usually still is, treated as waste material. After birth, it did its purpose, so after the newborn’s umbilical cord is cut it disappears in the bin. We also did this for years. What else should you do with a lifeless thing that looks more like a large bloody clot than an interesting organ. But nothing turns out to be less true. In the Placenta Lab, the most interesting and promising studies are performed on the placenta after birth. Research into how the blood vessels respond to medicines and abnormalities in these responses provide knowledge about new treatments that can be used during pregnancy. For example, in the near future we may be able to use medicines to treat the diseased placenta and thus improve the chances for unborn children.

Outside the medical world, the placenta has been believed in for much longer. For example, there are ancient rituals to bury the placenta to plant a fertile tree on top

of it, or to bake it as a delicacy and eat it as a family. This is probably where the Dutch name moederkoek (mothers’ cookie) comes from, suggesting that it is something edible. Processing the placenta into pills is however way more fashionable. This already appears to happen regularly and also fits better within the field of pharmacology, which this magazine is all about. Encapsulation is the name of this conversion of the placenta into capsules filled with processed placental material. People have claimed that such pills would reduce the risk of mood disorders and stress after birth. Possibly due to an increase in the happiness hormone 'oxytocin'. The iron content, which is often reduced in the mother after a bloody delivery, is also well supplemented with such a placenta pill. It may seem like a strange and unusual thought now, and of course, there are also decomposition and waste products in the placenta that should be filtered out. We already know that from the Placenta Lab.

In times of scarcity, when cradle to cradle is the future, maybe something like this should not simply be dismissed as quackery. In addition to treating the placenta, we may even be able to gain a better understanding of which medicinal substances it contains. The 'green delivery room' is the future, so no waste material, but food for thought!

WHY THIS RESEARCH?

Unlike most other organs in our body, like our heart, lungs and kidneys, we still do not know much about the placenta. With medical scientific research we try to discover how the placenta works in order to find (better) treatments for pregnancy-related diseases.

Preterm birth

If something goes wrong in the development of the placenta, it can cause preeclampsia: a disease in which a malfunctioning placenta secretes substances into the maternal blood causing high blood pressure and organ damage in the mother, as well as poor fetal growth. Still there is no good treatment available for preeclampsia, necessitating doctors to induce preterm birth of the child and the placenta in life-threatening situations. Although the mother's symptoms disappear quickly, the disease continues to affect the health of mother and child throughout the rest of their lives. It is therefore essential to develop a therapy for this serious condition.

De placenta offers opportunities

Since it is best to treat a disease at its cause, I studied how the preeclamptic placenta differs from a healthy one. The unique thing about the placenta is that its birth allows us to conduct research with human material, increasing the chance for it to have direct impact for clinical practice. This gives an advantage over medical scientific research that can only be conducted in cell or animal models, of which promising

THE FUNCTIONS OF THE PLACENTA

1. Delivery of nutrients and oxygen from the mother to the fetus

2. Removal of waste products from the fetus to the mother

AN ORGAN WITH TWO BLOODCIRCULATIONS

The placenta is an organ that consists of two blood circulations: that of the mother and that of the unborn child (the fetus). These two circulations flow past each other, allowing nutrients and waste to be exchanged, but they are never in direct contact with each other.

results are sometimes not as effective in the human situation.

In various sections of this magazine, I summarize the research I did during my PhD. New treatments for preeclampsia illustrates how we aim to improve the function of the placenta with existing medication. Alterations in the placental immune system describes how components of the immune system are altered in preeclampsia. Tryptophan, a nutrient with special functions in the placenta, depicts the metabolism and effects of tryptophan – a nutrient that we all take in through our diet – in the placenta in healthy pregnancies and preeclampsia.

THE EXPERIMENTS

PLACENTA PERFUSION MODEL EXPERIMENT

The placenta perfusion model is a system in which the placenta can be kept alive after birth. Normally the placenta contains blood of the mother and the child, but in this model the blood is replaced by a fluid similar to blood.

The placenta perfusion experiments are conducted under circumstances that mimic the condition in the mother's abdomen as closely as possible.

This means that the placenta and fluids are maintained at body temperature, and the perfusion fluid flows through the placenta at the same speed as blood would.

Using this model, the placenta is kept viable up until four hours after birth, enabling us to for example study the speed by which a drug moves from the blood of the mother to the child.

EXPERIMENT

BLOODVESSEL MYOGRAPHY

Blood vessels can widen or contract the action of smooth muscle cells in the vessel wall. This allows them to determine the amount of blood flow through the placenta.

We can investigate the ability of blood vessels to change their diameter in a wire myography set-up. In this device we can mount tiny pieces of blood vessels that are about 2 mm in length on iron wires and measure the tension that these blood vessel segments exert.

When the blood vessel contracts it is measured as an increase in force, while the force decreases when the vessel widens.

By cutting small blood vessels from the placenta after the birth of the placenta, we can therefore examine the function of these blood vessels using this wire myography device.

EXPERIMENT

PLACENTA CULTURE

The placenta can excrete all sorts of substances into the blood of the mother and the child. These substances are necessary for the mother and child to adapt to pregnancy. However, these substances can also have negative effects.

We can conduct research into the substances that the placenta secretes using placental explant cultures. For these culture experiments we cut small pieces of the

placenta immediately after birth. These pieces are then placed in a special medium and maintained in a stove that mimics the condition in the mother’s abdomen. The advantage of these experiments is that it is easier to keep pieces of placenta alive for longer periods of time, especially in comparison with the placenta perfusion model. This allows us to for example study the effects of medication for a longer period of time.

TENSION CONVERTER MICROMETER

THE STUDIES

NEW TREATMENTS FOR PREECLAMPSIA

Why this research?

These days, there is still no cure for preeclampsia. Even though doctors can provide symptom relieve through blood pressure lowering medication when a woman suffers from preeclampsia, it is still impossible to treat the actual cause of the disease: the placenta. When the disease becomes life threatening, doctors are forced to induce birth of the child and the placenta, often prematurely. It is thus essential to find new therapies that allow quick implementation into clinical practice. In reality the development of new medication takes a long time. However, there are certain types of medication that are already being used to treat other disease, and these drugs have properties that may be helpful in the treatment of preeclampsia as well. One such promising medication is pentoxifylline. Although a medication may seem promising, it is (luckily) not possible to just try it pregnant woman without a good incentive. As a first step we investigated how much pentoxifylline would reach the fetus, and how it would affect the placenta if the mother would be treated with pentoxifylline.

Most important findings

Using the placenta perfusion model, we found that pentoxifylline can easily transfer from the maternal tot the fetal blood. This means that when a pregnant women would be treated with pentoxifylline, the fetus would be exposed to the same concentration. As our perfusion

BLOOD, OXYGEN AND NUTRIENTS

The blood flow in the placenta is (partly) determined by the level of contraction of the blood vessels in the placenta. By controlling their diameter, these placental blood vessels regulate the amount of oxygen and nutrients that are transferred from the maternal blood to the blood of the fetus.

model does not enable us to study the potentially positive or negative effects on the fetus, this should be investigated in future studies. In the wire myography experiments we could however study the effects of pentoxifylline on the placenta. In these experiments we found that pentoxifylline widened blood vessels from both healthy and preeclampsia placentas. Interestingly, this widening was exerted through a different mechanism in preeclampsia compared with healthy placentas.

VIAGRA FOR THE PLACENTA

Pentoxifylline can widen blood vessels by inhibiting the enzyme phosphodiesterase (PDE). Sildenafil, better known as Viagra, is also a phosphodiesterase inhibitor. Sildenafil was first developed in 1989 for the treatment of heart disease. Unfortunately, the first clinical studies did not find significant improvements for the problems in the heart. During these studies, sildenafil was however reported to have a remarkable effect on the blood flow towards another organ. This proved to be such a large success that it could still be market.

Relevance

Pentoxifylline may improve the function of the placenta. Even though pentoxifylline does not preserve all its properties during preeclampsia, it still has positive effects. Pentoxifylline is unlikely to have negative impacts on the child at the end of pregnancy, as recent studies show it is useful for the treatment of sepsis in preterm born infants. Besides preeclampsia, pentoxifylline may also be an interesting therapeutic option for other pregnancy such as fetal growth restriction, threatening preterm birth, or inflammation in the placenta.

ALTERATIONS IN THE PLACENTAL IMMUNE SYSTEM

Why this research?

Women with preeclampsia have increased levels of inflammatory factors in their blood. Doctors and scientists have proposed this to be caused by inflammation in the placenta as a consequence of it impaired functioning, however, this was never properly investigated. Therefore, we studied the exact immune alterations in preeclamptic placentas. We looked at:

1. Differences in expression of 750 genes related to the immune system..

2. The release of inflammatory factors from the placenta into the blood.

3. The types of immune cells that were altered in the placenta.

Most important findings

In contrast to what we expected, many of the inflammatory factors were unaltered or even decreased in the placentas of women with preeclampsia. Whereas literature usually describes only one type of immune cell in the placenta –the Hofbauer cell – we discovered several types of immune cells in the healthy placenta: M1 Hofbauer cells, M2 Hofbauer cells and mast cells. Interestingly, placentas from women with preeclampsia contained fewer M2 Hofbauer cells and mast cells compared to healthy ones.

Relevance

By studying placental immune alterations, we can better understand how and why preeclampsia originates. It is essential to understand these alterations to develop safe therapies for preeclampsia.

GROWING SAFELY WITH AN OWN IMMUNE SYSTEM

The placenta has its own immune system that enables the baby to grow inside its mothers belly without being rejected. This is very special if you consider that organ transplantation necessitates the recipient to take a lot of medication to prevent rejection of the transplanted organ, even when the organ is from a family member. This is because normally our own immune system makes sure that intruders, especially pathogens, are eliminated from our body. During pregnancy, the specialized immune system of the placenta ensures that the immune system of the child and mother do not fight each other.

TRYPTOPHAN, A NUTRIENT WITH SPECIAL FUNCTIONS IN THE PLACENTA

Why this research?

Tryptophan is an essential nutrient that we all take in through our food. The amount of tryptophan that reaches the fetus is thus largerly determined by the amount of tryptophan that is eaten by the mother. Before tryptophan reaches the fetus, it first needs to cross the placenta where it can affect placental function.

The placenta can convert tryptophan into different substances with several functions via a chain reaction, all these substances together form the kynurenine pathway. From previous research we know that the first step of this pathway is altered in the placenta during preeclampsia. Unfortunately, data on the rest of the kynurenine pathway was still missing. As we expected that changes in the conversion of tryptophan through the kynurenine pathway could contribute to, or cause preeclampsia, we aimed to answer the following questions:

1. Where in the placenta is tryptophan converted through the kynurenine pathway?

2. How much tryptophan transfers from the mother to the fetus, or is converted into other substances in the placenta?

3. How is the conversion of tryptophan in the placenta altered during preeclampsia and how does this affect the function of the placental blood vessels?

NUTRITION

Proteins are made from amino acids. Our body can produce most of the amino acids, but there are nine amino acids that you need to obtain through your diet, the so-called essential amino acids. Tryptophan is one of these essential amino acids. Tryptophan is very important for the development of the fetus, however, the amount of tryptophan that reaches the fetus is determined by the amount of tryptophan the mother eats because the fetus receives all its food trough his/her mother. Examples of tryptophan rich products are milk, eggs, oats, peanuts, seeds, banana, chocolate, tofu, fish and chicken.

Most important findings

Through searching existing literature we discovered that the conversion of tryptophan through the kynurenine pathway requires not just one cell, but many different types of cells, to execute all parts of the pathway. This means that the formation of all parts of the kynurenine pathway are controlled by different cell types.

In the placenta perfusion model we confirmed that the placenta transports tryptophan from the mother to the fetus. We also discovered that the conversion of tryptophan by the placenta does not affect the concentrations of the products of the kynurenine pathway in the circulation of the mother and the child. This means that the concentrations of the kynurenine pathway products in the blood of the mother cannot be used as measure of kynurenine pathway activity in the placenta. These are important data, as this is in contract to what scientist believed and reported so far.

While studying the effects of tryptophan on the placental blood vessels, we found that the conversion of tryptophan into kynurenine (the first step of the kynurenine pathway) can induce widening

of the blood vessel. This step depends on the enzyme IDO1. Since the amount of this enzyme was reduced in the placentas from women with preeclampsia, we expected that the widening of the blood vessels would also be impaired. Yet, the widening of blood vessels in response to tryptophan was increased in preeclampsia compared to healthy placentas. We found that this was due to an increased uptake of tryptophan into the placenta during preeclampsia. Shortly summarized, placentas from women with preeclampsia could compensate for a reduced conversion of tryptophan into kynurenine by increasing the tryptophan uptake into the cells.

Relevance

Alterations in the conversion of tryptophan into kynurenine in the placenta may offer new opportunities for for the treatment of preeclampsia.

MAKES YOU HAPPY

Even though most tryptophan is (~95%) is converted into kynurenine, tryptophan is actually more famous as precursor of serotonin and melatonin. Serotonin is a substance that makes us happy, melatonin lets us sleep well.

HEALTHY PLACENTA PREECLAMPSIA PLACENTA

During pregnancy, the placenta is attached to the mother's uterine wall, allowing it to fill with the mother's blood. The child is connected to the umbilical cord, which branches into tiny blood vessels inside the placenta. These small vessels float, as it were, in the blood of the mother. The blood of the mother and the child are never in direct contact with each other. So in the image on the next page, the blood vessels drawn are those of the child, floating in the dark blood of the mother.

With our research we found that tryptophan, pentoxifylline and sildenafil can dilate healthy placental blood vessels, whereby pentoxifylline could also inhibit the secretion of inflammatory factors from the placenta. In addition, we discovered three different types of cells of the immune system in the healthy placenta. The exact role of these cells is still unclear, but they may contribute to the formation of the placenta.

In case of preeclampsia, something goes wrong in the development of the placenta, causing the blood vessels to contract. As a result, less oxygen and nutrients reach the placenta, causing it to excrete harmful substances. These substances can make the mother very sick. By dilating the blood vessels of this diseased placenta, we hope to improve the function of the placenta and reduce disease in the mother and child.

Our studies with placentas from women with preeclampsia showed that tryptophan, pentoxifylline, and sildenafil did not always produce the improvements we found in healthy placentas. This seems to be a disappointing result, but it also gives us useful information about what actually goes wrong in the placenta in preeclampsia. This knowledge is essential for future research to develop a treatment.

INDOLEAMINE 2,3-DIOXYGENASE

Can dilate bloodvessels by converting tryptophan into kynurenine

Degrades substances that can dilate blood vessels, sildenafil and pentoxifylline inhibit this enzym stimulating blood vessels dilation.

"WOULD YOU STILL LIKE TO USE HER PLACENTA?"

NEVER-ENDING

It has been a while since I had been waiting in the room next to the delivery room. With a white bucket in my hand and dressed in a blue transparent overcoat from the operation rooms and a not so charming hat, I started to feel very warm.

The operation rooms in the Sophia children’s hospital always have the thermostat just a bit higher that comfortable. Besides, I had been rushing. An hour ago, I was sitting on the bench in my living room reading the wind-up bird chronicle, a book of one of my favourite writers. Just when I reached the part where Toru Okada descents extremely slowly, step by step on slippery tennis shoes a rope ladder into an invisibly deep well, my phone rang. It may have been my own perception, but the sound of the phone seemed extra urgent. I had put my book down and walked to the dining table to pick up my phone. It was the resident physician of the gynaecology department. 'I hope I’m not disturbing you, but I noticed that Mrs Janssen is taking part in your studies. Her condition has just become worse and we are about to go to the operating room for a C-section. Would you still like to use her placenta?’. ‘Yes, thank you very much for calling. I'll be right there’ I said and hung up.

So now here I am, standing next to the delivery room waiting until the baby and

the placenta are born, still a bit sweaty from the cycling to the hospital quickly. The room I am standing in is separated from the operating room by a connecting door. This door has a window, and if I stand close to the door on the points of my toes I can just see through the window. It is busy in the operation room with doctors and nurses from the gynaecology, neonatology and anaesthesiology departments. I catch a glimpse of the baby being lifted from the mother's belly by the doctor. If I remember the pregnancy data correctly, this child is now born after a pregnancy of just 29 weeks. Fortunately, the baby starts to cry and I see a sigh of relief over the paediatrician

Michelle Broekhuizen

IN THE FUTURE

THESIS

PLACENTAL ORIGINS OF HEALTH & DISEASE

MAGAZINE

DUTCH VERSION

PLACENTA MAGAZINE