Visualizing The Placenta, a Critical but Poorly Understood Organ
Posted on by Diana W. Bianchi, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development
The placenta is the Rodney Dangerfield of organs; it gets no respect, no respect at all. This short-lived but critical organ supports pregnancy by bringing nutrients and oxygen to the fetus, removing waste, providing immune protection, and producing hormones to support fetal development.
It also influences the lifelong health of both mother and child. Problems with the placenta can lead to preeclampsia, gestational diabetes, poor fetal growth, preterm birth, and stillbirth. Although we were all connected to one, the placenta is the least understood, and least studied, of all human organs.
What we do know about the human placenta largely comes from studying it after delivery. But that’s like studying the heart after it’s stopped beating. It doesn’t help us predict complications in time to avert a crisis.
To fill these knowledge gaps, NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) developed the Human Placenta Project (HPP) to noninvasively study the placenta during pregnancy. Since 2014, this approximately $88 million collaborative research effort has been developing ultrasound, magnetic resonance imaging (MRI), and blood-based biomarker methods to study how the placenta functions in real time and in greater detail.
As illustrated in the image above, advanced ultrasound tools allowed HPP researchers at Eastern Virginia Medical School, Norfolk, and the University of Texas Medical Branch, Galveston, to gain a detailed look at the placenta’s intricate arrangement of blood vessels, or vasculature. By evaluating both fetal (left panel) and maternal (right panel) placental vasculature in 610 pregnant people starting at 13 weeks of gestation, the investigators aimed to identify early changes that predicted later complications.
They observed that such changes can start in the first trimester and affect both the vasculature and placental tissue. While further research is needed, these findings suggest that placental ultrasound monitoring can inform efforts to prevent and treat pregnancy complications.
Another HPP team led by Boston Children’s Hospital is developing an MRI strategy to monitor blood flow and oxygen transport through the placenta during pregnancy. Interpreting and visualizing MRI data of the placenta is challenging because of its variable shape, the tendency of muscles in the uterus to begin tightening or contracting well before labor , and other factors.
As shown in the video above, the researchers developed a way to account for the motion of the uterus and “freeze” the placenta to make it easier to study (left two panels of video) . They also developed algorithms to better visualize the complex patterns of placental oxygen content during contractions (center panel) . The scientists then carried out initial visualizations of blood flow through the placenta shortly after delivery (second panel from right) .
They now intend to map these MRI findings to the placenta itself after delivery (far right panel), which will allow them to explore how additional factors such as gene expression patterns and genetic variants contribute to placental function. Ultimately, they plan to apply these MRI techniques to monitor the placenta in real time during pregnancy and identify changes that indicate compromised function early enough to adjust maternal management as needed.
Other HPP efforts focus on identifying components in maternal blood that reflect the status of the placenta. For example, an HPP research team led by scientists at the University of California, Los Angeles, adapted non-invasive prenatal testing methods to analyze genetic material shed from the placenta into the maternal bloodstream. Their findings suggest that distinctive patterns in this genetic material detected early in pregnancy may indicate risk for later complications .
Another HPP team, led by investigators at Columbia University, New York, helped establish that extracellular RNAs (exRNAs) released by the placenta into maternal circulation reflect the placenta’s status at a cellular level beginning in the first trimester. To harness the potential of exRNA biomarkers, the investigators are optimizing methods to isolate, sequence, and analyze exRNAs in maternal blood.
These are just a few examples of the cutting-edge work being funded through the HPP, which complements NICHD’s longstanding investment in basic research to unravel the physiology of and real-time gene expression in the placenta. Unlocking the secrets of the placenta may one day help us to prevent and treat a range of common pregnancy complications, while also providing insights into other areas of science and medicine such as cardiovascular disease and aging. NICHD is committed to giving this important organ the respect it deserves.
 Placental MRI: Effect of maternal position and uterine contractions on placental BOLD MRI measurements. Abaci Turk E, Abulnaga SM, Luo J, Stout JN, Feldman H, Turk A, Gagoski B, Wald LL, Adalsteinsson E, Roberts DJ, Bibbo C, Robinson JN, Golland P, Grant PE, Barth, Jr WH. Placenta. 2020 Jun 1; 95: 69-77.
 Spatiotemporal alignment of in utero BOLD-MRI series. Turk EA, Luo J, Gagoski B, Pascau J, Bibbo C, Robinson JN, Grant PE, Adalsteinsson E, Golland P, Malpica N. J Magn Reson Imaging. 2017 Aug;46(2):403-412.
 Volumetric parameterization of the placenta to a flattened template. Abulnaga SM, Turk EA, Bessmeltsev M, Grant PE, Solomon J, Golland P. IEEE transactions on medical imaging. 2022 April;41(4):925-936.
 Placental MRI: development of an MRI compatible ex vivo system for whole placenta dual perfusion. Stout JN, Rouhani S, Turk EA, Ha CG, Luo J, Rich K, Wald LL, Adalsteinsson E, Barth, Jr WH, Grant PE, Roberts DJ. Placenta. 2020 Nov 1; 101: 4-12.
 Cell-free DNA methylation and transcriptomic signature prediction of pregnancies with adverse outcomes. Del Vecchio G, Li Q, Li W, Thamotharan S, Tosevska A, Morselli M, Sung K, Janzen C, Zhou X, Pellegrini M, Devaskar SU. Epigenetics. 2021 Jun;16(6):642-661.
Human Placenta Project (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)
Understanding Gestational Diabetes (NICHD)
Preterm Labor and Birth (NICHD)
Abuhamad Project Information (NIH RePORTER)
Grant Project Information (NIH RePORTER)
Devaskar Project Information (NIH RePORTER)
Williams Project Information (NIH RePORTER)
Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 10th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Progress Toward 3D Printed Human Organs
Posted on by Dr. Francis Collins
There’s considerable excitement that 3D printing technology might one day allow scientists to produce fully functional replacement organs from one’s own cells. While there’s still a lot to learn, this video shows just some of the amazing progress that’s now being made.
The video comes from a bioengineering team at Rice University, Houston, that has learned to bioprint the small air sacs in the lungs. When hooked up to a machine that pulsed air in and out of the air sacs, the rhythmic movement helped to mix red blood cells traveling through an associated blood vessel network. Those red cells also took up oxygen in much the way that blood vessels do when surrounding the hundreds of millions of air sacs in our lungs.
As mentioned in the video, one of the biggest technical hurdles in growing fully functional replacement tissues and organs is to find a way to feed the growing tissues with a blood supply and to remove waste products. In this study recently published in Science , the NIH-supported team cleared this hurdle by creating an open-source bioprinting technology they call SLATE, which is short for “stereo-lithography apparatus for tissue engineering.”
The SLATE system “grows” soft hydrogel scaffolds one layer at a time. Each layer is printed using a liquid pre-hydrogel solution that solidifies when exposed to blue light. By also projecting light into the hydrogel as a pixelated 3D shape, it’s possible to print complex 3D structures within minutes.
When the researchers first started, their printouts lacked the high resolution, submillimeter-scale channels needed to generate intricate vascular networks. In other manufacturing arenas, light-absorbing chemicals have helped control the conversion from liquid to solid in a very fine polymer layer. But these industrial light-absorbing chemicals are highly toxic and therefore unsuitable for scaffolds that grow living tissues and organs.
The researchers, including Bagrat Grigoryan, Jordan Miller, and Kelly Stevens, wondered whether they could swap out those noxious ingredients with synthetic and natural food dyes widely used in the food industry. These dyes include curcumin, anthocyanin, and tartrazine (yellow dye #5). Their studies showed that those fully biocompatible dyes worked as effective light absorbers, allowing the scientists to recreate the complex architectures of human vasculature. Importantly, the living cells survived within the soft scaffold!
These models are already yielding intriguing new insights into the vascular structures found within our organs and how those architectures may influence function in ways that hadn’t been well understood. In the near term, tissues and organs grown on such scaffolds might also find use as sophisticated, 3D tissue “chips,” with potential for use in studies to predict whether drugs will be safe in humans.
In the long term, this technology may allow production of replacement organs from those needing them. More than 100,000 men, women, and children are on the national transplant waiting list in the United States alone and 20 people die each day waiting for a transplant . Ultimately, with the aid of bioprinting advances like this one, perhaps one day we’ll have a ready supply of perfectly matched and fully functional organs.
 Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Grigoryan B, Paulsen SJ, Corbett DC, Sazer DW, Fortin CL, Zaita AJ, Greenfield PT, Calafat NJ, Gounley JP, Ta AH, Johansson F, Randles A, Rosenkrantz JE, Louis-Rosenberg JD, Galie PA, Stevens KR, Miller JS. Science. 2019 May 3;364(6439):458-464.
 Organ Donor Statistics, Health Resources & Services Administration, October 2018.
Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
Miller Lab (Rice University, Houston)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of General Medical Sciences; Common Fund
Snapshots of Life: Development in Exquisite Detail
Posted on by Dr. Francis Collins
If you’ve ever tried to take photos of wiggly kids, you know that it usually takes several attempts before you get the perfect shot. It’s often the same for biomedical researchers when taking images with microscopes because there are so many variables—from sample preparation to instrument calibration—to take into account. Still, there are always exceptions where everything comes together just right, and you are looking at one of them! On her first try at using a confocal microscope to image this cross-section of a mouse embryo’s torso, postdoc Shachi Bhatt captured a gem of an image that sheds new light on mammalian development.
Bhatt, who works in the NIH-supported lab of Paul Trainor at the Stowers Institute for Medical Research, Kansas City, MO, produced this micrograph as part of a quest to understand the striking parallels seen between the development of the nervous system and the vascular system in mammals. Fluorescent markers were used to label proteins uniquely expressed in each type of tissue: reddish-orange delineates developing nerve cells; gray highlights developing blood vessels; and yellow shows where the nerve cells and blood vessels overlap.