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Using MicroRNA to Starve a Tumor?

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Endothelial cells are inhibited from sprouting
Credit: Dudley Lab, University of Virginia School of Medicine, Charlottesville

Tumor cells thrive by exploiting the willingness of normal cells in their neighborhood to act as accomplices. One of their sneakier stunts involves tricking the body into helping them form new blood vessels. This growth-enabling process of sprouting new blood vessels, called tumor angiogenesis, remains a vital area of cancer research and continues to yield important clues into how to beat this deadly disease.

The two-panel image above shows one such promising lead from recent lab studies with endothelial cells, specialized cells that line the inside of all blood vessels. In tumors, endothelial cells are induced to issue non-stop SOS signals that falsely alert the body to dispatch needed materials to rescue these cells. The endothelial cells then use the help to replicate and sprout new blood vessels.

The left panel demonstrates the basics of this growth process under normal conditions. Endothelial cells (red and blue) were cultured under special conditions that help them grow in the lab. When given the right cues, those cells sprout spiky extensions to form new vessels.

But in the right panel, the cells can’t sprout. The reason is because the cells are bathed in a molecule called miR-30c, which isn’t visible in the photo. These specialized microRNA molecules—and humans make a few thousand different versions of them—control protein production by binding to and disabling longer RNA templates, called messenger RNA.

This new anti-angiogenic lead, published in the Journal of Clinical Investigation, comes from a research team led by Andrew Dudley, University of Virginia Medical School, Charlottesville [1]. The team made its discovery while studying a protein called TGF-beta that tumors like to exploit to fuel their growth.

Their studies in mice showed that loss of TGF-beta signals in endothelial cells blocked the growth of new blood vessels and thus tumors. Further study showed that those effects were due in part to elevated levels of miR-30c. The two interact in endothelial cells as part of a previously unrecognized signaling pathway that coordinates the growth of new blood vessels in tumors.

Dudley’s team went on to show that levels of miR-30c vary widely amongst endothelial cells, even when those cells come from the very same tumor. Cells rich in miR-30c struggled to sprout new vessels, while those with less of this microRNA grew new vessels with ease.

Intriguingly, they found that levels of this microRNA also predicted the outcomes for patients with breast cancer. Those whose cancers had high levels of the vessel-stunting miR-30c fared better than those with lower miR-30c levels. While more research is needed, it does offer a potentially promising new lead in the fight against cancer.

Reference:

[1] Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1. McCann JV, Xiao L, Kim DJ, Khan OF, Kowalski PS, Anderson DG, Pecot CV, Azam SH, Parker JS, Tsai YS, Wolberg AS, Turner SD, Tatsumi K, Mackman N, Dudley AC. J Clin Invest. 2019 Mar 11;130:1654-1670.

Links:

Angiogenesis Inhibitors (National Cancer Institute/NIH)

Dudley Lab (University of Virginia School of Medicine, Charlottesville)

NIH Support: National Cancer Institute; National Heart, Lung, and Blood Institute


Making Personalized Blood-Brain Barriers in a Dish

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Credit: Vatine et al, Cell Stem Cell, 2019

The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.

But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.

To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.

While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.

The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.

Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.

The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!

As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.

In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.

Reference:

[1] Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, Wen N, Spivia WR, Chen Z, Van Eyk J, Svendsen CN. Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Stem Cell Information (NIH)

Svendsen Lab (Cedars-Sinai, Los Angeles)

NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences


Snapshots of Life: The Brain’s Microscopic Green Trash Bins

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Zebrafish brain

Credit: Marina Venero Galanternik, Daniel Castranova, Tuyet Nguyen, and Brant M. Weinstein, NICHD, NIH

There are trash bins in our homes, on our streets, and even as a popular icon on our desktop computers. And as this colorful image shows, trash bins of the cellular variety are also important in the brain.

This image—a winner in the Federation of American Societies for Experimental Biology’s 2017 BioArt competition—shows the brain of an adult zebrafish, a popular organism for studying how the brain works. It captures dense networks of blood vessels (red) lining the outer surface of the brain. Next to many of these vessels sit previously little-studied cells called fluorescent granular perithelial cells (yellowish green). Researchers now believe these cells, often shortened to FGPs, act much like trash receptacles that continuously take in and store waste products to keep the brain tidy and functioning well.


Snapshots of Life: Development in Exquisite Detail

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Developmental biology

Credit: Shachi Bhatt and Paul Trainor, Stowers Institute for Medical Research, Kansas City, MO

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.


Snapshots of Life: Green Eggs and Heart Valves

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three-day old chicken embryo

Credit: Jessica Ryvlin, Stephanie Lindsey, and Jonathan Butcher, Cornell University, Ithaca, NY

What might appear in this picture to be an exotic, green glow worm served up on a collard leaf actually comes from something we all know well: an egg. It’s a 3-day-old chicken embryo that’s been carefully removed from its shell, placed in a special nutrient-rich bath to keep it alive, and then photographed through a customized stereo microscope. In the middle of the image, just above the blood vessels branching upward, you can see the outline of a transparent, developing eye. Directly to the left is the embryonic heart, which at this early stage is just a looped tube not yet with valves or pumping chambers.

Developing chicks are one of the most user-friendly models for studying normal and abnormal heart development. Human and chick hearts have a lot in common structurally, with four chambers and four valves pumping two circulations of blood in parallel. Unlike mammalian embryos tucked away in the womb, researchers have free range to study the chick heart in or out of the egg as it develops from a simple looped tube to a four-chambered organ.

Jonathan Butcher and his NIH-supported research group at Cornell University, Ithaca, NY, snapped this photo, a winner in the Federation of American Societies for Experimental Biology’s 2015 BioArt competition, to monitor differences in blood flow through the developing chick heart. You can get a sense of these differences by the varying intensities of green fluorescence in the blood vessels. The Butcher lab is interested in understanding how the force of the blood flow triggers the switching on and off of genes responsible for making functional heart valves. Although the four valves aren’t yet visible in this image, they will soon elongate into flap-like structures that open and close to begin regulating the normal flow of blood through the heart.


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