Measuring Inflammation in the Placenta in real time: Conversation with Dr. Yong Wang, Part I

The placenta is critically important for the success of a pregnancy, being the physical connection between the mother's body and the developing fetus. Defects in the placenta tend to have significant consequences for the pregnancy and the fetus, including things like preeclampsia, preterm birth and maybe also congenital heart defects. So understanding what's going on in the placenta before these conditions develop has enormous potential to drastically improve the health of the fetus and future child. But figuring out that a problem is a foot before physical signs of that problem show themselves in the form of preterm contractions or high blood pressure in pregnancy has been a challenge. Today I'm talking to a researcher I'm describing as the Magellen of pregnancy, an explorer of sorts showing us new details of changes in inflammation during pregnancies in progress that we haven't been able to see before by adapting a specific type of MRI to image inflammation in the placenta in real time.

To read the paper, you can find it here: https://pmc.ncbi.nlm.nih.gov/articles/PMC11698687/

Transcript

Paulette: [00:00:00] The placenta is critically important for the success of a pregnancy being the physical connection between the mother's body and the developing fetus. Defects in the placenta tend to have significant consequences, 

For the pregnancy and the fetus.

including things like preeclampsia, preterm birth, intrauterine growth restriction, and maybe also congenital heart defects.

So understanding what's going on in the placenta before these conditions develop has enormous potential. To improve the health of the fetus and future child. But figuring out that a problem is afoot before physical signs of that problem show themselves in the form of preterm contractions or high blood pressure in pregnancy has been a challenge.

Today I'm talking to a researcher I'm describing as the Magellan of Pregnancy, an explorer of sorts showing us new details of changes in inflammation , during pregnancies in progress that we haven't been able to see before by adapting a specific type of [00:01:00] MRI to image inflammation in the placenta in real time.

Welcome to Making Sense of Pregnancy. This show is a new pregnancy reference. I'm finding and talking with experts doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own experience. Each week I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in reproduction, giving you the most current.

Evidence-based way to approach this enormous transition in your life. I hope it will become your go-to source for how to make your pregnancy better. Please enjoy the first part of my conversation with Dr. Yang Wang. I.

Today we're lucky to have Dr. Yong Wang back on the show., He's a professor of everything. He's a professor of radiology, of biomedical engineering. And on your webpage it also says of obstetrics and gynecology. Earlier this year we spoke about the technology you were adapting from cardiology to measure.[00:02:00] 

The electricity moving through a contracting uterus, which is super cool. I dare say, may be rivaled by what we're gonna talk about today, but all of them unbelievably cool. Today we're gonna talk about using a special form of MRI to measure inflammation in the placenta. Thank you so much for coming on Dr.

Wang. 

Dr. Wang: Thank you for invitation. 

Paulette: So today the paper we'll talk about for anyone interested in more detail is called quantitative and Longitudinal Assessment of Human Placental Inflammation using Diffusion Basis Spectrum Imaging. And that was published in January of this year in the Nature Portfolio Women's Health. Let's jump into this super cool paper and technology that you're using right now, by talking first about, , what your quote unquote fixing. What do we do right now to scan the placenta? 

Dr. Wang: Sure. So currently we primarily use conventional T two weighted MR.

And ultrasound to assess placental structure and morphology, so those [00:03:00] technologies can identify major anatomical anomalies. things like placental abruption, you know, placental previa, and gross structural defects. However, they are quite limited in detecting functional problems or inflammatory processes.

It's like having a photograph of a building but not knowing what's happening inside the rooms. So we can see if the structure looks normal, but we cannot access the cellular processes that often drive pregnancy complications and outcomes. So this is why so many placental issues and problems are only detected after complication occurs.

So our current imaging tools are , really not sensitive enough to detect early pathology changes, particularly related to placental inflammation. 

Paulette: , when I read this paper, I feel like what I'm hearing is what it feels like to walk on the moon for the first time 

Dr. Wang: because, , I think this is our initial ambitious goal [00:04:00] because imaging inflammation in the placenta is very difficult in vivo, in patient longitudinally.

'cause the tools we have for human body inflammation imaging. Uh, largely was implemented in the brain, in the heart, but most of them re rely on, you know, contrast agent to enhance Yep. The contrasting MRI or you are using radioactive treaters for PET imaging. Yeah. Both are not safe for the woman during pregnancy and not safe for fetus for for sure.

So we need something really noninvasive, safe, and you can do longitudinal measure during this critical pregnancy period. So it's very challenging, but I, I agree with you. This is something, we are uniquely targeting this special needs in in pregnant women. 

Paulette: I mean, , it's amazing. And let me try and, in nearly a sentence, summarize sort of what we have.

So ultrasound is shooting sound waves into the body and using a program to measure what those organs look like based on how [00:05:00] the sound waves reflect, right? That's 

Dr. Wang: right. 

Paulette: Okay. Very generally speaking, MRI is using a magnet to get the water molecules in your body to behave a certain way, and then ping the molecules with a radio frequency and watching their reaction, the reaction of the tissues. That have more and less water to trace out the boundaries of these organs. And this approach is kind of measuring water content in the tissue so that the organs with high water content appear bright. And the organs with low water content appear darker.

But DBSI is something different. Are we measuring how the water moves when the cell is pinged? How? How? What are we doing with DBSI? Right? 

Dr. Wang: Yeah. Happy to talk about about more details. 

Paulette: Yeah. 

Dr. Wang: So DBSI is one special type of MRI. It's called diffusion, MRI.

So in general, most of the MRI techniques are using, , the proton signals, basically the signal generated, , by the water molecules inside our body because it's very abundant in our [00:06:00] body. , So compared to traditional MRI, which is trying to measure the relaxivity of the water molecules after our RF house injection, diffusion, MR is trying to measure how the water molecules moves inside our body.

This is called a Brownian motion motion in our high school physics. 

Paulette: Okay, a brief interruption here. In the event that you are not remembering what Brownian motion is from high school physics, it describes the random jerky movements of microscopic particles suspended in either liquid or gas, and that's caused by continuous invisible collisions with the molecules surrounding it.

So if you are seeing a larger particles that appear to dance around in a random way, what you aren't seeing is the much smaller unseen particles constantly bumping into the larger visible particles. And we're talking about brownie motion because this will be important in diffusion, MRI. And to the [00:07:00] extent that I understand this diffusion, MRI is able to discern the cellular level details of the tissue because it's using the movement of water

to infer microscopic tissue details that can't be resolved with standard imaging. So when water diffusion is restricted, like inside or around cells, the MRI signal changes in characteristic ways. And this provides information on cell density, size, shape, and orientations which are invisible to conventional.

MRI.

Dr. Wang: Yeah. So if you can measure those brown emotions and use the brown emotions as a probe to measure the geometrical structures of our cellular,, structures in our human body. But conventionally the diffusion MRI does not have the capability to tell the subvoxel, so microstructure inflammation.

So which limit is sensitivity and specificity to tell inflammation from other [00:08:00] microstructures? Right. We are stuck there for long, long time. So based on this gap, so DBSI was designed to fundamentally be different because it can separate multiple tissue components. Within the same imaging voxels based on their unique diffusion signatures.

So I want to put an example for you to better understand. So think of it like having a mixed drink. Conventional MRI gives you the average color of the whole mixture, like de diffusion, sensor imaging, diffusion weighted MR imaging. But DBSI can tell you exactly how much of each ingredient is present.

Specifically DBSI model tissue as a containing different compartments like large cells, smaller cells like immuno cells and actual cellular space, and each with very distinct diffusion properties or signatures. So the key advantage is that immuno cells in the placenta are much smaller than other [00:09:00] placental cells.

So they are so they can restrict water diffusion differently. This allow us to create specific maps of immuno cells infiltration, something that was impossible with previous techniques, including traditional diffusion MRI 

Paulette: th this is looking room to room in each house. In the inside the house. Right. It's it, it is inside, so, exactly, 

Dr. Wang: exactly.

Inside the house. The traditional diffusion MRI can tell you, for example, overall. Like what's the, a average age of those persons in the room? But they can now tell you how many of them are from like younger group, like teenagers. Yeah. How many are adults from 20 to 40 years old? How many are senior persons? But now, DBSI have the capability to tell them apart, which give us much better capability to tell, okay, there are 5% of immuno cells in those tissues.

Right? So that's very valuable information. We want to, we want to generate from this technology. 

Paulette: So we're looking voxel by [00:10:00] voxel, which I think is a measurement of the image. H how, how big is a voxel? Is there any way to. 

Dr. Wang: That's a great question. So on clinical scanners, because considering we cannot put patient in a scanner forever, so normally we want to constrain the, the imaging time within 10 minutes.

So with that constraints, the most popular clinical special resolution is run the two millimeter cubic. If you have. Maybe longer scanning time. You can push downward to one millimeters, but one to two millimeter cubic is the traditional, pretty standard clinical spatial resolution. 

Paulette: Just a note here, and I feel like we're all taking so many pictures. Maybe this makes intuitive sense, but voxel size is important because it speaks to accuracy. We wanna know the size of the volume we are averaging over. Smaller volume may give a more accurate picture, but then you're also using less information, so you may need a longer scan.

And Dr. Wang [00:11:00] touches on this where the scan currently is 10 minutes, but they could consider making it longer to to increase the signal to noise ratio. Okay. , That's amazing.

, In your paper you mentioned that part of the use of this technology will be to look at inflammation in the placenta, and you mentioned all these different conditions that arise from the presence of different immune cells like neutrophils create a certain condition and basophils, are present in a different condition, but right now we can't distinguish which immune cells are present.

We just know it's immune cells as opposed to other cells in the placenta. 

Dr. Wang: I think you are absolutely correct. So at this moment, uh, the first generation of DBSI application on placenta cannot distinguish between different types of immuno cells, like you mentioned, a neutrophils and other like a macrophages.

So the technique at this moment identify cells based on their size and the diffusion properties. So most [00:12:00] immuno cells luckily fall within a smaller cell range, about six to 20 micros. In, in placenta, which is much smaller than other resident, uh, placental cells that are normally bigger than 50 micrometers.

So this is not the case in the brain. In the brain you have much , wide spectrum of cells. But in the placenta, luckily. All the immuno cells looks significantly smaller than is resident placental cells. So this has gave us a foundation to be able to tell what's the inflammation. But in order to distinguish different specific cell types, we are thinking to combine DBSI findings with complementary information such as.

Blood biomarkers, plasma biomarkers, maybe other specific MRI Contrast agent or other spectroscopy technologies. Uh, so the spatial resolution will need to be improved also by at least one other magnitude so that we can do better cell specific contrast. [00:13:00] Imaging. So another new technology, , not really new 20 years old, that we can change the diffusion acquisition protocols by reducing the diffusion time.

So that already shows some promise. We can measure the cell size better, , which better sensitivity, so which can give us maybe another opportunity to better tell the cell types based on their size. But that will be our next step of work. 

Paulette: So it sounds like even more refined pictures may be on the horizon, which is totally exciting. I guess one thing that confused me when I read this paper the first time is 

Dr. Wang: yeah, 

Paulette: I'm imagining the placenta is set up in a certain way where you're not supposed to have mom's ma immune cells inside the placenta.

Well, I guess maybe you are at birth or we're not sure whether you're at birth, but, but when , the placenta is up and running at 12 weeks right. I thought that, yeah. It's created to keep this barrier between mom's blood and the baby's blood. So why are there immune cells in the placenta?

Is that [00:14:00] alone a signal that something's gone wrong? 

Dr. Wang: Oh yeah, you are. You are, , absolutely correct. So the maternal fetal circulations are separate, right? Yeah. , So in our paper we talk about a technique based on , T two star weighted images and diffusion weighted images. We can basically decompose or segment in automatic fashion.

We can segment the whole placenta into placental tissue, , placental vessel and intervillous space, , automatically so we can quantify their cellularity structures, immuno inflammations within these three different compartments, which can give us much better idea. What is the inflammations in the placental itself and what happens in the placental tissues?

And that can give us a lot of ideas like what happened on the maternal side and what happened , on the fetal side. So this is, , something will be, like you mentioned, it's very interesting and what will be very important to see how maternal fetal communicate to each other, but with this type [00:15:00] of, , segmentation.

We could refine our DBSI measurements to give us much better, more specific, in indexes to study fetal maternal communications. But again, this is, will be probably our future studies, uh, we'll based on the findings within this first paper. 

Paulette: One more quick note here. To give you a visual sense of what we're talking about. , This episode should come with a map. , If you picture the cross section of the placenta, you have a semicircle with an umbilical cord coming outta the top, and in the semicircle that looks kind of like a smile. You have these tree-like structures, so the placental tissue are those trees. Placental vessels are the fetal blood vessels inside the trees, and the interval of space is the maternal blood filled space between the trees.

 And do we imagine since you're getting at this super interesting and critical spatial, , aspect of the inflammation, that [00:16:00] maybe there's information in where the immune cells are residing?

Dr. Wang: Uh, yes. Based on our funding in the paper, I think a lot of the, uh, inflammatory cells are really living in the placental tissue itself. That's the most popular place you will see those, , immuno cell infiltration. And the second popular space is the vessels around the vessels within the placental, tissues we call placental vessel compartment.

And in the intravenous trees in the vous space, you, you won't see much inflammatory cells. So you do see some spatial, distribution signatures or differences within the human placenta over the pregnancy. So we see that, uh, basically consistently, like this type of spatial distribution is pretty, pretty consistent across different gestational age during pregnancy.

Paulette: Yeah. That's . Another thing that's cool about this study is that not only did you look in pregnant women, you, you imaged actual pregnant women, [00:17:00] but you did it over time at these Yes. At these different time points. Yeah. So that to me is super cool. So can you talk a little bit about. The differences between,, women who had placentas that had inflammation and women who did not.

Dr. Wang: Sure. Sure. So this is again, one of the advantages. If you have a tool which can imaging placental inflammation safely so that that way you can apply that repeatedly over pregnancy because pregnancy is a highly dynamic process and it really require a longitudinal follow-up. So DBSI really fulfill this, , ideal target because we are pretty safe.

We are , using the, , water within our body. As a probe to study the inflammation. So ideally, uh, we want to scanning, , the patient to be able to understand the key developmental transitions and the critical decision points. So we really prefer, if possible, to scans at eight to 10 weeks of the gestation to capture early [00:18:00] implantation process and how new, , placental inflammation may play the role in this process.

Also 16 to 18 weeks during major placental VA vascularization stage, and also 24 26 weeks while many complications first manifest, and later on at 32 or 34 weeks for late pregnancy risk assessment. So those longitudinal time point ideally will capture the major phases of the placental immuno development while providing very clinically actionable informations for clinical decision making.

But current schedule, , we show in the paper at 12, 20, 32 to 36 weeks, all while they are very convenient because patient come in for real regular, uh, OB cares, but may meet some early pathology processes that began in the first trimester, which is quite challenging to image. But that will be our probably next step of work to add on early stage imaging.

Paulette: Yeah, I was hoping for a scan, a really early first [00:19:00] trimester scan to see more of the immediate results of implantation. I, maybe you can't do anything with, there is no placenta, but maybe you can't do anything that early. But I, I wonder if, , your schedule makes more sense than the OB schedule right now.

, I don't know what the current schedule is organized around. Right.

 , Or maybe a better way to say that, is that the current OB schedule is organized around the technology. We have to detect trouble and progress in a pregnancy, and as we get more exact technology like this diffusion, MRI and have more biomarkers, the OB visit schedule may might reflect different possible intervention points.

I am gonna stop my conversation with Dr. Wang here for today. I so appreciate that. He took the time to walk us through how this technology diffusion basis spectrum imaging was used to examine brains and hearts originally and can be adapted to measure the placenta in a safe and non-invasive way.

There are ways to [00:20:00] measure elements of the placenta right now using ultrasound.

T two weighted MRI Doppler and even CT scans have been used and those things have been used to look at blood flow in the placenta, but looking at the actual inflammation in the placenta in real time could provide early warning about inflammatory conditions that may lead to things like preeclampsia, preterm labor, or placental dysfunction, and it could identify inflammation even when blood flow has not been affected yet when blood flow appears normal. and data that we can use to check on whether a medication regimen is working. There's much more to say on this topic, but I'll save it until next week's episode. 

If you like this episode, please share it with friends or rate and review. The show ratings really help because it makes it easier for other people to find the show. We'll be back next week to talk more about using diffusion MRI to measure inflammation, and we'll talk specifically about how it worked in the pregnancies in Dr.

Wang's [00:21:00] study.