The miracle of pregnancy and new life with Dr Lana McClements

Welcome to Science in Focus. A free public lecture series showcasing the latest research from prominent UTS scientists. I'm Jim MacNamara, Deputy Dean of the UTS Faculty of Science in accordance with custom. I would like to acknowledge the Gadigal people of the Eora nation upon whose ancestral lands our city campus now stands. We pay our respects to their elders past and present, and acknowledge them as custodians of traditional knowledge about this place. Today, it is my pleasure to introduce Dr. Lana McClements, who is speaking on the miracle of pregnancy and new life. Lana is a lecturer in biotechnology in the UTS Faculty of Science. She researches women's health with a particular focus on understanding pregnancy complications, such as preeclampsia. Her research has had significant impact in creating new monitoring strategies for women who are at risk. We are pleased to present Dr. Lana McClements.

Hello, I'm Laura McCaughey, and I'll be the moderator, for today's event, collecting questions and asking our speaker, Dr. Lana McClements, questions both during and at the end of her talk, I'll now hand over to Dr. Lana McClements to hear about her fascinating research into pregnancy and its possible complications.

Thank you very much, Laura. Hello, everyone. I'm delighted to be able to talk to you about pregnancy and also my research, which is in relation to pregnancy complications. So I'd like to start my talk by showing you a picture of myself with my second born daughter. This is two days after I've delivered Emily and I looked very happy and relieved at the same time. But I'm not sure if you can notice. I do have a bit of a yellow tint in my face, even though this is this is one of the two most happiest days of my life. The first one being with my first born. So the events coming up to it were a little bit stressful, to say the least. So I actually was diagnosed with gestational diabetes in pregnancy. So this was my second time that I had gestational diabetes because I also had it in my first pregnancy. It was a bit of a shock in the first pregnancy because I didn't expect it. I did expect it in the second pregnancy because there is increased risk of developing it, developing it sort of in, when you when you have had it in your first pregnancy.

But in addition to this, I also developed towards the end of my pregnancy obstetrical cholestasis , which is the liver dysfunction often linked to the hormone secreted from the placenta. And we'll talk about the placenta in great detail later on as well. That obviously meant that I have to have induced labor. My children were not premature, so they were full term, but I was lucky. The good news was that they didn't have preeclampsia. So you will realise, you will learn about preeclampsia today in my talk, whilst I had quite a few other complications, preeclampsia was not one of them. So we'll go back to the very start and will give you an outline of actually how pregnancy starts with embryogenesis. So I'd like to thank my talented honours student, Claire Richards, for providing these pictures to me. So this is part of the female reproductive system and this is the ovary where ovum or 'egg' gets released. It travels down the fallopian tube to meet sperm cells. So spermatozoid, which actually then implants, fertilizes the egg and travels down definitely a particular tube and gets implanted into the uterus. But during this travel from sort of meeting the the egg to actually implanting itself into the uterus, there are quite a lot of changes happening. So following a fertilisation, zygote is formed, which is a single cell which contains fusion of sperm cells and egg cells. And these zygote undergoes a number of divisions until it forms 'morula'. Morula is a structure that contains about sixteen cells at this point that have been divided and containing both genetic material from the mother and the father.

And then further on, on day six, a blastocyst is actually developed, which contains all of these cells. But as you can see, it's a little more organized structure and it contains outer layer of differentiated trophoblast cells. Now, remember this name 'trophoblast' cells, because we will talk about them a lot. They actually end up remodelling maternal vasculature to allow supply of oxygen nutrients to the baby. But also they form this organ called placenta. There is this inner cellular mass within the blastocyst where the foetus will be formed from. The rest of the blastocyst is actually filled with fluid that will form on the attack on the amniotic fluid that will keep the baby floating inside. And mothers and stock interests. So what happens then. Well, once we have the blastocyst form, it travels down fallopian tubes to reach the uterus. And these trophoblast cells on the outside of the blastocyst are quite sticky. And they secrete, they secrete chemicals that actually attach to these endometrium, which is the lining, the mucus lining of the uterus. So whilst the blastocyst actually attaches to the endometrium. It travels down. And these trophoblast cells then start dividing and forming this layer of cells that travels further down to actually reach a spiral uterine arteries of the mother and trophoblast... what happens then is that trophoblast actually invade these foreign uterine arteries, remodel them, which is our next part of the talk. This is the cross-sectional and the magnified section of this spiral uterine artery within the uterus or the myometrium of the uterus.

So normally in a non-pregnant state, these spiral uterine arteries are just sitting at normal, they are supplying uterus with blood and oxygen, nutrients, etc. But in pregnancy, so once the blastocyst travels down to the endometrium trim and then further down to the myometrium, which is this part of the uterus, it actually starts to remodel these spiral uterine arteries by allowing trophoblast cells, which formed the outer layer of the blastocyst that we talked about in the previous slide. And what this does actually allows for these spinral uterine arteries to remodel, and to become elastic and to allow and restrict the supply of oxygen and nutrients to the placenta and then further the baby. But what this means for the woman's body is that there are a lot of changes. So both cardiovascular and metabolic changes. So some examples of these include an increase in maternal blood flow hundreds of times, which is substantial. As you can appreciate, blood volume also increases 30 to 50 percent and heartbeats increases 10 to 15 beats per minute to meet the demands of all these changes and the growing fetus. So until placenta develops from these trophoblast cells and what placenta actually does is delivers oxygen and nutrients to the baby so the baby can grow in utero and also removes waste products. But also another important function of it is partial protection of fetus from teratogens and pathogens in the maternal circulation, I would like to thank my other honor student, Ingrid Ataman, for providing this to me for this presentation.

What is interesting is that placenta is actually an endocrine organ. What this means is that it actually secretes hormones to substantiate the development of the fetus. So the hormones that are secreted include estrogen, cortisol and human placenta lactation. So what these hormones do, while they do wonderful things, and enable pregnancy, really, the progression of pregnancy. They also have the function of inhibiting the insulin and the work that insulin does within the body.

So insulin is not very effective anymore in utilizing and breaking down glucose and metabolism. So that means that women actually have to produce more insulin from their pancreas, which is at this leafy structure underneath the liver.

But in some women, this is actually not managed very well. The body can manage this excess insulin demand and this develops into gestational diabetes mellitus. Gestational diabetes occurs all in pregnancy, and it is a major concern nowadays, particularly because there is increased risk of obesity. And nowadays, with a change in the lifestyle and the number of women actually having Type two diabetes as well before pregnancy is increasing to. So currently, over 21 million women have some form of diabetes in pregnancy. So we could easily say that hypoglycemia or the presence of high blood glucose in pregnancy is actually one of the most common complications in pregnancy. And this complication in pregnancy does lead to increased size, increased baby size because actually glucose passes through the placenta very easily and it can be easily absorbed by the baby. However, this leads to sort of increase in the size of the baby.

But it's not a good thing, actually, because fat around your organs can be formed and other complications as well. And in fact, what we've been seeing over the last 10 years is a two to six fold increase in the incidence of gestational diabetes.

So what are the complications of gestational diabetes and macrosomia, which means a big size of the baby that can cause complications during delivery, such as so shoulder dystocia but also other complications, such as preeclampsia and preeclampsia is the focus of these talks. And my research as well, in addition to preeclampsia, I also research diabetes as a risk factor for pregancy.

So what is preeclampsia? Preeclampsia is the leading cause of maternal and fetal death in the world, and it affects about five to eight percent of pregnancies. The number of women experiencing preeclampsia in pregnancy actually is on the rise because there is increased number of women with obesity and diabetes.

Also, after preeclampsia or after the pregnancy has been finished.

And women are at increased risk of developing future cardiovascular diseases and also diabetes. And two out of three women will actually die from cardiovascular disease. Cardiovascular disease in general is the biggest killer in the world, accounting for 31 percent of deaths. Even more in cancer. But these women in particular increased risk in the future. So it needs to be monitored closely. Knowing all this, it is shocking that we actually don't have any any effective treatments or effective monitoring strategies for women who have preeclampsia, at pregnancy and afterwards as well. This is the area that we focus on. So preeclampsia still kills over 70,000 women and five hundred thousand babies every year. Most of these deaths actually occur in developing countries, and this is because women don't have access to care so easily and they live in remote areas. The health care systems are not very well developed, etc. and that leads to fatal consequences. Short term complications from preeclampsia during pregnancy includes preterm birth. And these this is general. This is before 37 weeks of gestation. HELLP syndrome, which is the hemolysis, elevated liver enzyme and low platelets, a very dangerous syndrome that lead to organ damage and other complications as well. Eclampsia, eclampsia are seizures, which can also be fatal. Stroke. Neonatal respiratory distress syndrome is another short term complication associated with preeclampsia and long term, like I said in the previous slide, it's diabetes. Women have increased risk of diabetes, cardiovascular disease and stroke as well. It is possible that these some of these women already had sort of underlining risk factors for developing these diseases later on in life that actually get unmasked during pregnancy. So actually, whilst pregnancy is a stress test for the body, it's also an opportunity for intervention early on to prevent any complications and death further in the future.

To make things even more complicated, they're actually two, at least two in fact, phenotypes of frequency that we know of. We are still research and trying to understand this condition better. But what we know so far is that there is early onset preeclampsia and there is late onset preeclampsia. These two types of preeclampsia are subdivided according to the time of gestation of their diagnosis. So, for example, early onset preeclampsia is diagnosed before 34 weeks of gestation, and it is normally associated with difficult complications in placental development and also intrauterine growth restriction, just as small babies, in fact, whereas late onset preeclampsia, which is which actually consists 80 to 90 percent of preeclampsia cases, a lot more case women would have this type of preeclampsia, that early onset preeclampsia. Whilst it's potentially milder, it actually occurs after thirty four weeks of gestation. And often it is not associated with placental placental complications and restrictions in the growth or the development, in fact. But still, it is... There are some overlapping features between the two different types of preeclampsia. Hence it is not so straightforward to identify one or the other type. Also preeclampsia, what we know so far is often associated with sort of underlining complications such as diabetes and obesity and other vascular complications in pregnancy. And I'd like to thank Ingrid again for providing this slide for me.

So how does preclampsia develop what we know in terms of sort of placental development, where placenta is actually involved in its development, is that if you remember from our blastocyst slide where we had our trophoblasts that traveled down the spiral uterine artery to remodel it. So in normal pregnancy. This is done properly. And the spiral uterine arteries are remodeled. They're wide, they're elastic, and there is unrestricted supply of oxygen. and nutrients to the placenta and the baby. However, in preeclampsia, this process is actually restricted, leading to a restricted supply of oxygen and nutrients to the baby potentially restriction in the growth of the baby, but also other complications, because what these trophoblast cells have to do. And these are fetal cells, if you remember, from the blastocyst that we talked about earlier on, they have to remodel this artery. And by remodeling, they actually have to interact with endothelial cells.

Now, endothelial cells are cells that line the blood vessels in our vasculature through through which blood actually flows and supplies various organs, including placenta and the baby in pregnancy.

So these endothelial cells, if they're not functioning well because there is an underlying vascular risk factors that women have without ever knowing, it can cause this inappropriate development of the placenta. Also inappropriate spinal uterine artery remodeling, as we call it. But if the fetal cells, on the other hand, as well are not functioning well, this can cause problems, too. And therefore, a lot of our research will actually focus on identifying factors that can influence the function of the trophoblast cells, but also the function of the individual cells as well. So before we go on, I'd like to pass you on to Laura for any questions that you might have to break down the talk into two sections.

Thanks for a fascinating introduction into pregnancy Lana, we've had a lot of questions come through the Q&A and also from the event registration. And I'll try and get through as many of these same will permit. Our first question is from Deb, and she wants to know. Do we know what causes preeclampsia?

That's, that's a great question. Thank you very much Deb, for asking that.

So a lot of the mechanism and the causes of preeclampsia are unknown. We're still trying to to investigate and understand why this happens. So that is the big problem, why we haven't really been able to come up with very effective preventative treatments or curative treatments and also monitoring strategies. But what we do know is that diabetes, for example, is a risk factor and that can lead to and that increases the risk of preeclampsia. So, for example, women who have pre-existing diabetes before they become pregnant, they have up to fourfold increased risk of preeclampsia. If a woman has a higher BMI as well, that is a risk factor, too. Sometimes. And age can be also of older age, but is not a significantly increased risk. But it is associated with the risk of preclampsia and other auto immune diseases, chronic hypotension, for example. It is interesting the first time mothers actually have a sort of background increased risk of preeclampsia, rather than the second time of it, for example. So there are some things we know about it. But there is also a lot that we don't know and we need to find out going forward.

I have another question that you touched upon there. The question is, is there a higher risk for people who are older? And if so, why?

So that there is an increased risk potentially of preeclampsia as you get older and age is one of the risk factors, too, generally over 40 years of age. We don't really know exactly why this happens. It could be to do with the vasculature and sort of more stress that the body has gone through and the aging process itself.

But again, it's not it's not very well understood. And we are trying to sort of understand how these aging processes can actually affect and are linked to it. Again, coming back to vasculature there is sort of underlining the issue with the vasculature and the fetal cells are not working so well, etc. That could be one of the reasons, too.

We had two questions from Marina. She wanted to know, what does a one hundred fold increase in blood flow mean? Do you mean that it circulates faster? And also, could you clarify what you meant by two out of three women who have had preeclampsia will die of cardiovascular disease?

Sure. No problem. Thank you, Marina. So a hundred blood fold... actually, more blood is produced to substantiate the development of the fetus. So the body has to go through all these changes, more haemoglobin in the red blood cells, etc. So it's it's a fascinating machinery, really. And what women's bodies going through. In terms of future. So. So as I said, cardiovascular diseases are actually the leading cause of death in for everybody. So the 30 percent of deaths account for... come from cardiovascular complications.

So these women, for women, cardiovascular disease, anyways is the number one killer too, but because preeclampsia can actually cause this inflammation and oxidative stress and will go in the second part of my talk about these sort of stress factors that can remain after pregnancy and therefore lead to damaged to blood vessels, etc, that can lead to cardiovascular disease.

We've got a question from Kathy, and she wants to know what are the first symptoms of preeclampsia to watch out for?

That's a great question. Very difficult. Preeclampsia is sometimes also very difficult to diagnose. It's not  straightforward in some women we have typical symptoms. Symptoms of high blood pressure. So high blood pressure is what one of the compulsory, you would call them symptoms. But in addition to high blood pressure, there has to be other symptoms as well. Otherwise, if it's only high blood pressure in pregnancy, that's called gestational hypertension. So in addition to high blood pressure, we also have organ damage, for example, kidneys or liver. So if there is any liver function tests showing a sort of abnormal results or for example, there is protein in the urine where it shouldn't be, damaged kidneys are not working so well, etc. Other symptoms, in addition to high blood pressure, could be a headaches, swelling in the feet around the ankles and other, other organ damage.  Platelets could be also affected. In addition. And it is generally, what is why we are working so, so hard to actually try and figure out the way to monitor women from the early pregnancy and to pick up preeclampsia early is because it comes on so suddenly. In a lot of the cases, the pregnancy is going really well, nothing is wrong. And also then all of a sudden, all this happens and women end up in the hospital, etc.. So we are trying to actually find a way that we can monitor it from early on in pregnancy so that we can diagnose any changes or foil any changes early on without complications and sudden onset of severe symptoms and early birth of course.

Thanks, Lana. I'll let you tell us about your research now. And we'll have some time for more questions at the end.

Thank you very much. Right.

So we'll go on about the details of of my research and the research of my team. Of course, it's a team of collaborators and collaborators and students and postdocs students to help with this research. So our focus is actually trying to understand the mechanisms underlining preeclampsia, what happens early on in pregnancy with a placenta or with other cells. That then leads to the development and manifestation of preeclampsia later on in pregnancy. Bearing in mind that pregnancy, that preeclampsia gets manifested sort of after 30 weeks of gestation, any time after 20 weeks of gestation actually can occur, but in most cases, it will be after 30 weeks of gestation. So we are actually investigating some novel proteins and microRNAs. MicroRNAs are a small nucleic acids that regulate translation of genes into proteins and proteins are very important because they actually are key for the changes in our bodies. So whatever is the result of molecular changes actually comes through changes in the protein expression or differences in the function of those. So we are using placenta as a model, and to understand any molecular changes and how these can be leveraged and used for developing, for example, tests. Inflammation being one of the one of the very common undermining process in preeclampsia as well. So we are understanding how these proteins in my property can affect information, lead to development of inflammation, etc. Angiogenesis is the vascular development. So obviously there is a lot of angiogenesis happening in the body during pregnancy because extra blood is needed to supply a fetus. Endothelial dysfunction. So cells that line the blood vessels and we talked about as well, we want to understand how these proteins and microRNA affect their function and also cellular processes, because all these cells trophoblast, endothelial cells and other cells that are actually present within the placenta. And these include sort of other cells such and such as mesenchymal stem cells, immune cells, etc. They all have down the road proliferation and differentiation. So maturation as well. And aptopsos is a celld death, really.

So obviously there is increased cell death potentially in preeclampsia that we are trying to understand why this happens and what regulates these processes.

So I just wanted to show you some of our work. So this is this the cross section of the placenta. So we took a little chunk from the placenta, from a mother who delivered a baby and placenta is a massive big organ. And so, therefore, a really expensive tissue to be, to be investigated and used for for research purposes. And what we did actually, we made little slides of these placental tissue and we looked at the expression of trophoblood cells and also blood, blood vessels or endothelial cells that line our blood vessels. So this is how placenta looks inside. It's actually composed of many of these Chorionic villi, which are surrounded by trophoblood cells. And within these chorionic villi, we can see blood vessels as well, which are shown on this picture. So, for example, when we want to look at the differences in the expression between one one or many proteins that we are interested in, we can actually look at the differences in the expression of these proteins in healthy placenta versus placenta.

That was from a woman with pre-eclampsia. And this picture just depicts an example of how this particular protein is actually overexpressed, increased in preeclampsia compared to healthy pregnancies.

So because it's very, it's not so easy to get early placental tissue during pregnancy. The procedures are invasive and it's not something that we can do routinely. We're trying to actually develop models of the placental development in the lab using trophoblast entity or cells. So this is the work of my very talented honours student  Claire Richards. She actually was trying to develop these mini placentas into tissue. So it's a 3D. This is a 3D placental structures and composed of trophoblood cells. The first trimester trophoblood cells that actually organized themselves into these spheroids or organoids. And you can see that there was we've stained them with different proteins to show the nuclei of the cells or to show other features of the cells that are important in the development of these sort of mini placentas. When we actually take those out of the culture and cross-section them, so we cut the company in half or across. And we looked at inside the cells to see whether we have different types of cells. And it's not just one type of cells because it is the multi-tier rock called organized structure of the placenta. We actually realize that we have many different cell sizes within each spheroid or organoid. Some are bigger. Some are smaller.

Therefore, we have the heterogeneity in terms of the same structure.

But further work that I've done with Professor Warkiani from biomedical engineering is to try and develop these mini placentas in a more dynamic way. So having sort of been able to kind of see the development and measure changes in real time as cells interact. So what we are doing at the moment, we're trying to culture these trophoblast series that I showed you on the previous slide together with endothelial cell so we can mimic what's actually happening with the with this with placental development, inspiring uterine artery remodeling where these cells actually interact together. So this is a fascinating platform that Professor Warkiani actually has in his lab where we can put many different cell types on this chip. So it's almost as if we're building placenta on a chip. And we can put these in the single cells in the middle, for example, trophoblood cells on the side and or other cells that are of interest to us, as well as other treatments or collect super natans, which will contain changes in the protein expression that we can use as biomarkers. All of these then represents sort of more dynamic structure, and we are using this to elucidate and... Mechanisms affecting early preeclampsia and also early placental development, but also to test some treatments that we could potentially develop and use either to prevent preeclampsia or to treat preeclampsia. A specific project that we've been interested in elucidating its role in preeclampsia is called FKBPL. So we started this work five or six years ago. And we realized that all these processes that have been well-established in preeclampsia, including impaired vascular response or antiangiogenic response, which means restricted vasculature, also abnormal trophoblast invasion or abnormal trophoblast function oxygen changes when there is sort of restricted vascular development and there is obviously low oxygen potential and we call this hypoxia or reduced oxygen concentration and inflammation of the immune system play a big role. And actually, this protein that we are interested in plays role in all of these processes. And we have been exploring its role as a biomarker, but also potentially as a treatment for preeclampsia too.

So we filed two patents in relation to this work, which are currently being commercialized and validated and developed further as new tests of preeclampsia. So what we propose with our biomarkers and we have developed an advanced algorithm, not just including one protein, but a couple of proteins and other critical characteristics, they can actually we can identify changes in these, in the level of these proteins in combination with clinical features such as blood pressure, or proteins etc.. And then when we measure this sort of towards between second and third trimester, which is still sort of before preeclampsia develops, we see that the increase levels of this of these proteins. And then when preeclampsia is actually diagnosed, the ratio goes down. So if we can detect these changes early on before full blown preeclampsia occurs and manifests, we could potentially do something about it and reduce premature births and deaths, even if it just means monitoring women closely and giving symptomatic relief therapy as well. It can prevent complications.

So because most of these deaths associated with preeclampsia occur in developing countries due to poor access to health care and monitoring, etc., the best way to actually translate these tests into something that can be beneficial for all women and babies all around the world is to develop a digital health solution, which means that remote monitoring is something women can actually do from home and be monitored remotely by the clinicians or the health care team who can then intervene if they see any changes in various parameters that could stipulate that there is something going on that could indicate preeclampsia. So our proposal is to sort of be able to connect many monitors and also point of care devices. Point of care devices means that it could be like a pregnancy test... In the form of a pregnancy test. But it could be lined with various sort of proteins that we think could have a role in preeclampsia. So therefore, at home, patients can do their own testing and upload this information onto the app or the cloud where clinicians can remotely check it.

And then others patients, if there are any changes that could be indicating development of preeclampsia.

And then we've be doing this work at UTS with another collaborator of mine, Professor Dayong Jin. And he has a fascinating platform as well. Point of care test platform that can be translated into so many different diseases in testing and monitoring among many different diseases.

We've been working on actually translating our biomarkers into this platform that then can be incorporated at this digital health. This work is still in early stages, but t is promising.

So then shifting gears, we want to monitor women in pregnancy and also, detect if there any changes which can prevent serious complications. But actually one of the treatments, can we actually treat preeclampsia? How can the all of this be prevented or treated? And like I said, there are no effective treatments so far.

But what we do have is a limited, limited therapies. So, for example, aspirin, low dose aspirin calcium are used in some cases in high risk pregnancies, for example, that we know have underlying high risk of developing preeclampsia, such as, for example, women with diabetes.

However, aspirin has been shown to reduce the incidence of preeclampsia, but mainly of early onset preeclampsia. So that is a low stronger for that. And not so strong for late onset preeclampsia, which, if you remember, actually consists of 90 percent of preeclampsia cases. Calcium is also used as a supplement for women who have particularly lower calcium level in the blood. So if they have normal calcium levels, it might not work so well if they have lower calcium levels. So these are two options that we currently have and a lot more is in development. And then what happens when preeclampsia gets diagnosed? There is high blood pressure, there is organ damage. Then all we can do really is symptomatic relief. So we give we can give women the potential to bring their blood pressure down. Magnesium can work well for that as well. Just to kind of get a get a pregnancy to term so that we can prevent this preterm birth, which is associated with complications.

And often we don't have a choice but to deliver the baby and the placenta, which in most cases would stop.

But again, there is that residual risk of future complications. So we've been working on this novel Treatment Strategies, which consists of using mesenchymal stem cells and they secreted vesicles which have a lot of beneficial effect. At this pre-clinical stage, it hasn't been tested in human, but it has been tested in various models of the disease. So Mesenchymal stem cells, are probably one of the widest used stem cells. Some stem cell type tech therapies at the moment. And there one of the safest stem cell therapies at the moment. Many clinical trials in different diseases have been carried out with these type of stem cells. They can be isolated from adipose tissue, placenta itself or bone marrow. And what we've kind of been realizing over the last few years is that these mesenchymal stem cells actually don't necessarily differentiate and form different types of cells, but rather secrete these vesicles called extracellular vesicles that contain all the proteins and microRNA and sort of all the genetic cargo that has all these beneficial effects and therefore can improve the anti genesis or can improve that vascular restriction that can happen in preeclampsia. It can reduce inflammation. And also it can act as an antioxidant as well, potentially reducing the symptoms and curing this condition in preclinical models of preeclampsia.

They have been shown to have a beneficial effect and to be able to induce hyper high blood pressure and an organ damage. And we have actually recently reviewed this in the current hypertensive reports. If anyone is interested, you can look at our paper on this.

So what happens after preeclampsia develops and the baby's delivered and preeclampsia, this appears, there's that residual risk of cardiovascular disease that women are.

That two out of three women will actually die from the future. So cardiovascular disease is the single biggest killer in Australia, but also worldwide accounting for up to 30 percent of deaths.

So women who have had preeclampsia after preeclampsia is gone and the baby is delivered a few years later, even within the first five years postpart, they have three point seven fold increased risk of developing hypertension and a two point two fold increase risk of developing heart attack, for example, or ischaemic heart disease and one point eight percent and one point eight fold increased risk of stroke.

So therefore, what we should be doing really when women have suffered preeclampsia in pregnancy, we need to make sure that we are following them really well more closely in the future and trying to prevent or delay or manage these diseases better. So there is surprise.

We have been working on this paper, which is also published in the study with collaborators from Queens University, Belfast and also Mayo Clinic, where we wanted to look at the overlapping mechanisms between pre-eclampsia, hypertension, and HFpEF, which is heart failure with preserve ejection fraction. It's a form of heart disease. So because we know that these women have increased risk of cardiovascular, well, cardiovascular diseases in the future, we don't actually know what the mechanisms are. Again, coming back to the molecular levels and understanding what happened so that we can actually leverage this knowledge and develop tests or treatments, etc. And we have identified about 30 different mechanisms that could be overlapping and therefore they are worth pursuing further and trying to sort of understand, understand these links better and develop tests, for example, or treatments for that matter.

But other work that we've been moving, developing in collaboration with another colleague from biomedical engineering at UTS, Dr Carmine Gentile. He's trying to develop cardiac spheroids and so similar to what we're doing with our placentas, developing mini placentas, he wants to develop hearts in the dish. So Dr. Gentile has this amazing platform that is capable of bioprinting, these cardiac spheroids, and they're shown here.

So it's, again, that they would represent heart tissue by using blood from patients that can be converted into stem cells. And stem cells are pluripotent so they can give rise to many different types of cells. And by using a patient's blood, for example, to develop and make these stem cells, we can actually then make these stem cells produce other cell types which are a main or key cell types within the heart. And these include cardiomyocytes, endothelial cells and cardiac fibroblast, these three cell types of very important within the heart tissue and cardiomyocytes in particular, they compose most of the heart cells on tissue.

So we mix these three different cell types in a tube, for example.

And then they organized themselves and formed these sort of heart, cardio spheric, mini heart tissue that we can then use to understand mechanisms again. Or we can test some treatments to see whether certain treatments were working in a certain group of patients or not.

And this is sort of just by using blood from women post preeclapmsia for example, post complications in pregnancy so that we can understand if they have any if they will have any complications. Future complications, cardiovascular disease.

And then when Dr. Carmen stained these cardiac spheroids, then you can see that they are there cardiacmyocytes are actually in the red and they consist most of these cardiac spheroids. And then the green on the cardiac fibroblast and the blue endiothelial cells. And they organize themselves very similarly to what we would see in real heart.

So it's it's an excellent model for trying to investigate the mechanisms, biomarkers, but also treatment strategies for women who are at risk of developing cardiovascular disease post preeclampsia, for example.

So in summary, what I've sort of tried to give you an overview of pregnancy and our research and what we've been actually working on in my lab with many collaborators. So we are working on a new test for preeclampsia based on a novel mechanism that we think we can leverage to potentially early diagnose preeclampsia or monitor women from early on in pregnancy. We have developed or we are developing actually the heart and placental tissues that are representative of the human tissue. And we are also trying to understand the mechanisms between pre-eclampsia and future cardiovascular complications so that we can develop better monitoring and treatment strategies for these women and working on new treatments as well to treat preeclampsia and pregnancy, which are related to mesenchymal stem cells and secretive visicles. So this work doesn't happen very easily, and simply, and by myself.

So a lot of collaborators are involved and students in this work and would like to thank them all for all their effort and excitement to actually work on these projects and many different universities and organizations here in Australia, but also abroad also involved.

So thank you for listening and for attending my webinar as part of the UTS Science in Focus events. The webinar will be recorded and available on this link.

So I'll take now some questions from the audience, is there any further questions.

Thanks Lana. That was a really interesting talk. And we do have many, many questions from the audience. First question came from two different people, very similar question from Dana and Pada. Are there any groups or subpopulations of people who are more susceptible to preeclampsia? And is there anything that can be done to prevent it

So the women with diabetes, for example, particularly with type one and type two diabetes, which has developed before pregnancy, not as a result of pregnancy, would have increased risk of preeclampsia. Also, some women with auto immune diseases or if they have chronic hypertension before preeclampsia kicks in. They would be at increased risk of developing preeclampsia. So in this in these women that we know, when they when they come in for their twelve weeks plan or early on in pregnancy to obstetricians, we actually, they would normally be started on aspirin.

Aspirin is the only really preventative treatment there is to potentially prevent in high risk women in preeclampsia. But again, it's not so effective. That is the problem or particularly is effective for early onset preeclampsia, preeclampsia rather than late onset preeclampsia. So what we are trying to focus on that. We're trying to just increase that monitoring in women using low-cost and remote monitoring. So just by monitoring the blood pressure closely and most women wouldn't because they wouldn't know or it wouldn't be at risk of developing anything, they could potentially pick up these changes. So it doesn't mean that everybody should be doing that. But if anybody is at increased risk, if they're tested and they have increased risk, for example, of developing preeclampsia, they should be monitored closely, for example. And that can that would mean that they could they could diagnose it and prevent complications and preterm birth. Also another another way of sort of trying to not prevent and to reduce the risk will be by not making sure that women do not put a lot of weight in pregnancy as well. So the weight is managed well.

Traditionally, it's been thought that, you know, we can eat whatever you want in pregnancy. But as it is, you can see from right from my talk, there are a lot of hormonal and metabolic changes and cardiovascular changes. So weight has to be sort of managed well, whilst obviously it has to be a certain amount of increased weight if it's too much. That's also not good.

Are there any ethnic groups that are more likely to develop diabetes or preeclampsia?

Yes. So generally ethnic groups such as, for example, you know, Aboriginal and Torres Strait Islanders in Australia are indigenous groups that they tend to have increased risk, not just necessarily of preeclampsia, but a diabetes in pregnancy and beforehand. And that could be sometimes linked as well to the increased risk of increased levels of BMI.

And also, sort of some genetic predisposition to and if there is some, there is a familiar link as well with preeclampsia. So, for example, if if a mother or anybody else in the family had preeclampsia in their pregnancy, then that could potentially be also a risk factor for preeclampsia in your own pregnancy.

We've got another question from two people that's very similar. And have you tested FKBPL in urine from pregnant women? And could this be done like a pregnancy test, or do you need to use blood for your tests?

So far, we've only done it based on blood. So we still have to obtain blood. We haven't really measured it into yurine. Right. We don't know if we can pick it up into your urine. Urine of course, will be the least invasive way of doing it. But because women are getting blood tests done for various things throughout pregnancy, especially a 20 week scan and 20 week checkup. Then it wouldn't be necessarily an extra as a blood sample, but it will be sort of part of the regular regular monitoring.

Do you think that the increase in telehealth due to COVID-19 will help encourage the use of apps like the ones you've described?

That's a great point. It has actually come, it's coming to light with COVID-19, they are really promoting the use of digital health and telemedicine. And in fact, they they they have acknowledged that as a service that that clinicians can actually provide and get reimbursed for. Which is a big step forward for digital health. In fact, and I think it is now is the time when it when we realize how important this is. I mean, just going by my personal experience when I had gestational diabetes in my both pregnancies. I had to go in every week or every two weeks and that would have required half a day off work and two hours travel each way and then two hours wait in overcrowded waiting rooms and areas just to see somebody for ten minutes. So I would much rather have done this from home whereas I can still be monitored by by a clinician and escalated if I neeed to be but actually sitting at in the comfort of my own home or even from work.

Do you think there could be any risk of over monitoring by nervous first time mothers if they can do it themselves in their homes?

That is very true. And that is one of the points that we have to acknowledge, is that I guess, as a limitation because everybody's quite nervous in pregnancy, especially first pregnancy, everything's going well, etc.. So, yes, there is tha, but again, clinical staff will advise what is the most optimal number of test or monitoring points that you have to report. For example, for blood pressure it could be twice a week for blood glucose. For women who have gestational diabetes or onset diabetes, they will have to monitor their blood sugar six or seven times a day. That's a lot of breaks and difficult. So it's just it is just how, you know, you have to do it whatever the clinicians actually advise you to do it.

We've got a question from Alison, and she wants to know how are microRNAs being explored in preeclampsia.

Are you focusing more on their role as biomarkers or their biological roles in the development of preeclampsia?

So whilst biomarkers are actually generally used as a test to predict the likelihood of a disease or to actually diagnose diagnose a disease. They also give good insight into the mechanism and why this is happening. So they have the most of the time they have biological role. In some cases, it could be just an association and not necessarily a mechanism of the disease, but a lot of the time there would be a biological link as well.

There's a follow on question from that, from Glenna, and she wants to know, would you be transecting cells with extra cellular vehicles containing specific microRNAs to promote or demote specific protein translation?

Yes. So what we do generally, we collect these extracellular vesicles from the secreted medium or mesenchymal stem cells. And then we add them onto the cells. But we can certainly manipulate the protein or protein or RNA,  or microRNA expression, if we find that MicroRNAs will make these vesicles more effective. That is also possible to do before we actually put them on the cells and test them.

Another question from Alison is what is the reason for Proteineuria in preeclampsia? Is it due to damage of the kidneys or the blood vessels and the kidneys?

Sure. So proteins shouldn't be present in the urine. And so when the kidney actually filters all these proteins, it puts them back into the body, essentially. So if the proteins are present in the urine, obviously certain amount is OK. This is above an allowed amount then that can suggest that there is damage to the kidneys.

It could be many different causes of that. But it's generally the glemroical damage, which is the small cells or small cells within the kidneys which is due to many, many different reasons. But it could suggest kidney damage. Obviously, the kidneys are not actually filtering these things efficiently.

Any long term risks associated with preeclampsia for the baby and has a genetic link been observed?

Yes. So actually, everything that I've talked about, including the risk of future cardiovascular diseases for the mothers, the same risks are actually applicable to the offspring and the children as well. So there is increased risk of developing cardiovascular disease, diabetes, obesity, etc. for the offspring as well because of this, because fetal reprogramming, intrauterine fetal reprogramming that happens during pregnancy.

So we have a question here and it is whether the stem cells that you talked about need to come from the mother or whether they come from an anonymous donor. And then also, are stem cells safe to give to pregnant women?

So stem cells.

Actually, there's some evidence that mesenchymal stem cells in particular, that we are interested in, in women with preeclampsia. They have actually impaired function. So this is the work that has been done by our collaborators in the Mayo Clinic. In fact, Professor Garwich and her team, and they actually take out and extract these mesenchymal stem cells from the adipose tissue following the birth of the baby. And they have shown by characterizing the function of these cells, of these cells appear to have a different or impaired function. So hence that might suggest that it will be better to use a healthy donor mesenchymal stem cells from a bank, for example. And more so using these secreted vesicles from the stem cells will be an even better option in the future, because it is it will be a cell free therapy. So any risks or problems that are associated with this cell based therapies would then then disappear as well. Again, we are a long way from knowing exactly how safe these will be in humans, in human trials. But we are, there are a number of preclinical trials that are showing promising results.

Excellent. We've got a question here from Marilla, and she wants to know what is the difference between diabetes and gestational diabetes?

So gestational diabetes occurs in the second half of pregnancy. So women would develop it in pregnancy as a result of placenta secreting those hormones and the body not being able to adjust and generally disappears after the pregnancy is finished and the baby is delivering, a placenta is out, whereas other types of babies, such as type one diabetes and type two diabetes, they develop sort of outside of pregnancy in women who are not pregnant. And  that's the main difference. Now, gestational diabetes can sort of turn into type two diabetes after the pregnancy is certain in sort of 30 to 40 percent of women who have had it or sometimes in pregnancy, the type two diabetes can get unmasked because of the tests and the stresses that the body's going through. That wasn't diagnosed before pregnancy. So that is the main difference.

We've got a personal question for you here. Given your knowledge about how scary the complications in pregnancy can be. Were you worried at all about having babies?

Absolutely. I was terrified in both my pregnancies, but I'm that kind of a person as well, I worry too much about things. Tt was a worry.

But I think you just kind of had to trust clinical staff and people who are monitoring me. I was lucky to go to the same hospital with my first and the second one so they have my records. And they they knew my history from the first pregnancy. So this was monitored closely because I had gestational diabetes in my first pregnancy. So I would certainly recommend that if you are changing hospitals to make sure they have the full history from the first pregnancy, for example. So I was worried and I just was hoping that the second one would be better, but unfortunately wasn't. So now I'm done. 

If you experience preeclampsia and your first pregnancy, what is the probability in your second and subsequent pregnancies?

Great question. There is increased risk. So if you had preeclampsia in the first pregnancy, there is increased risk for having it in the second. Again, you have to, your  clinical staff and people looking after you, obstetrics and gynecology, the staff from the antenatal clinic and other health professionals. They would, they should have that information and then they would, if you have any concerns, by all means, speak to them because they will manage it the best, in the best way possible. So there is. 

What are your thoughts on the placenta's medical benefits post pregnancy?

And a very controversial field. A lot of it is unknown. So I really couldn't really comment too much about it.

Is their a genetic link to preeclampsia?

There is so I mentioned that I think earlier that if so, this is somebody in your family, your mother or aunt, would have had pre-eclampsia, there is increased risk. So if you are worried about a thing like that, to me, if there is I guess preeclampsia runs in the family, then you should most certainly speak to, speak to the doctor who's looking after you during pregnancy. And they would generally ask you these questions anyway as part of the first checkup. So speak to them and they will answer all your questions and concerns you might have.

Are there any treatments to be preeclampsia once you've been diagnosed with it?

That is the problem with preeclampsia, that we don't have sort of treatments that will cure the condition and that would cure sort of all these apparent processes that are happening and all these problems that are happening with the vasculature, with other cardiovascular effects. But the only option, once somebody is diagnosed with preeclampsia is to manage the blood pressure with antihypertensives. And there are certain types of antihypertensives that can't be used in pregnancy because they're dangerous for the baby. So there is an approved list of that antihypertensive drugs, which can be used for the margins of preeclampsia, but they would only really manage symptoms until the woman is ready to give birth. It's in the halls of strategy will be around trying to delaying that, prevent preterm or premature birth, really. So this is an area that certainly needs to be improved and researched more. And we have to come up with better and more effective treatments to actually cure this condition.

You mentioned that diabetes contributes to an increased risk of preeclampsia. But does it work in the other way if you have preeclampsia? Are you an increased risk of diabetes further down the line?

Absolutely. So preeclampsia increases the risk of future cardiovascular diseases, but also diabetes in both mother and offspring. So there is a risk. So whilst there is a risk for preeclampsia and general diabetes in adult life is a risk for future cardiovascular diseases is all intertwined and interlinked. And a lot of it is unknown. But certainly the epidemiological link between preeclampsia and future cardiovascular diseases such as diabetes has been established.

If apoptosis is reduced, preeclampsia, then will that impact on other disease states that are controlled by apoptosis?

So quite often. Again, this is under, under research and still a lot more that we don't know about it. But there is an increase in, you know, apoptosis potentially of trophoblast cells. So we are trying to actually prevent this from happening, whereas, for example, in some other conditions, such as cancer, we have tried to kill cancer cells. It's sort of the opposite of what we're trying to achieve here. Prevent that apoptosis.

How does nature or nurture influence gestational diabetes and preeclampsia? What lifestyle choices can help with dietary deficiencies that may contribute.

Sure. Very good question.

The gestational diabetes is very much, links to obesity and high body mass index. So there are some studies which have shown that in women who are at risk, for example, of gestational diabetes in general, for example, that have had gestation liberties in the first pregnancy, and they will be naturally at increased risk of it in the second, pregnancies, if they lose weight or manage weight better before pregnancy, and bring their glucose control within the required and desirable limits. That that reduces the risk in preeclampsia. So by managing your blood glucose and your body weight well and eating healthy and balanced diet, which allowed exercise, preventing that sedentary lifestyle, all of these things have shown to improve healthy outcomes of preganancy

Do you know anything about the implications of COVID-19 on a fetus's growth and development?

It's a very hot topic at the moment, and unfortunately, there's not much evidence coming through.

So far it has been reported that there is not necessarily an increased risk than any other pregnancy, but this is still to be confirmed and firmed up as more women, pregnant women actually have it. And we have better evidence to support these these findings. I mean, in terms of influenza, for example, influenza can be or for the flu, for example, it can be dangerous for the baby and the pregnancy and the mother as well. So pregnant women are encouraged to have their flu vaccines during pregnancy to prevent themselves in the flu. But in terms of COVID-19 so far, the reports are saying that it's not any more dangerous than the general population. But still to be determined.

You've talked about mesenchymal stem cells and they are different according to their different types of tissue, their stage and the proteomic or genomic profiles. So what types of cells were you planning to use?

So we've been working on in particular on bone marrow derived mesenchymal stem cells, bone modernized mesenchymal stem cells actually have been the most widely characterized.

And they're  being used in clinical trials for patients with different conditions, not necessarily in pregnancy, but sort of outside of pregnancy for cardiovascular disease, respiratory diseases, etc. And they're sort of the gold standard ones that we will refer from. But a lot more work now is being done with the umbilical cord-derived mesenchymal stem cells. They're the second most popular ones. And then also adipose tissue and the placneta itself.

So far, we've been working with bone marrow. But we are planning to also use the placental derived stem cells in the future, research and articles derived stem cells as well.

Well, thank you for a brilliant talk today, Lata. And thank you to everyone who attended. So thank you again for joining us. And have a great afternoon. Thank you, everyone.