Stem cell stories that caught our eye: drug safety for heart cells, worms hijack plant stem cells & battling esophageal cancer

Devising a drug safety measuring stick in stem cell-derived heart muscle cells
One of the mantras in the drug development business is “fail early”. That’s because most of the costs of getting a therapy to market occur at the later stages when an experimental treatment is tested in clinical trials in people. So, it’s best for a company’s bottom line and, more importantly, for patient safety to figure out sooner rather than later if a therapy has dangerous toxic side effects.

Researchers at Stanford reported this week in Science Translational Medicine on a method they devised that could help weed out cancer drugs with toxic effects on the heart before the treatment is tested in people.

In the lab, the team grew beating heart muscle cells, or cardiomyocytes, from induced pluripotent stem cells derived from both healthy volunteers and kidney cancer patients. A set of cancer drugs called tyrosine kinase inhibitors which are known to have a range of serious side effects on the heart, were added to the cells. The effect of the drugs on the heart cell function were measured with several different tests which the scientists combined into a single “safety index”.

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A single human induced pluripotent stem cell-derived cardiomyocyte. Cells such as these were used to assess tyrosine kinase inhibitors for cardiotoxicity in a high-throughput fashion. Credit: Dr. Arun Sharma at Dr. Joseph Wu’s laboratory at Stanford University

They found that the drugs previously shown to have toxic effects on patients’ hearts had the worst safety index values in the current study. And because these cells were in a lab dish and not in a person’s heart, the team was able to carefully examine cell activity and discovered that the toxic effects of three drugs could be alleviated by also adding insulin to the cells.

As lead author Joseph Wu, director of the Stanford Cardiovascular Institute, mentions in a press release, the development of this drug safety index could provide a powerful means to streamline the drug development process and make the drugs safer:

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients. It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects”

Worm feeds off of plants by taking control of their stem cells
In what sounds like a bizarre mashup of a vampire movie with a gardening show, a study reported this week pinpoints how worms infiltrate plants by commandeering the plants’ own stem cells. Cyst nematodes are microscopic roundworms that invade and kill soybean plants by sucking out their nutrients. This problem isn’t a trivial matter since nematodes wreak billions of dollars of damage to the world’s soybean crops each year. So, it’s not surprising that researchers want to understand how exactly these critters attack the plants.

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A nematode, the oblong object on the left, activates the vascular stem cell pathway in the developing nematode feeding site on a plant root. Credit: Xiaoli Guo, University of Missouri

Previous studies by Melissa Goellner Mitchum, a professor at the University of Missouri, had shown that the nematodes release protein fragments, called peptides, near a plant’s roots that help divert the flow of plant nutrients to the worm.

“These parasites damage root systems by creating a unique feeding cell within the roots of their hosts and leeching nutrients out of the soybean plant. This can lead to stunting, wilting and yield loss for the plant,” Mitchum explained in a press release.

In the current PLOS Pathogens study, Mitchum’s team identified another peptide produced by the nematode that is identical to a plant peptide that instructs stem cells to form the plant equivalent of blood vessels. This devious mimicking of the plant peptides is what allows the nematode to trick the plant stem cells into building vessels that reroute the plants’ nutrients directly to the worm.

Mitchum described the big picture implications of this fascinating discovery:

“Understanding how plant-parasitic nematodes modulate host plants to their own benefit is a crucial step in helping to create pest-resistant plants. If we can block those peptides and the pathways nematodes use to overtake the soybean plant, then we can enhance resistance for this very valuable global food source.”

Finding vulnerabilities in treatment-resistant esophageal cancer stem cells

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Illustration of radiation therapy for esophageal cancer.
Credit: Cancer Research UK

The incidence of esophageal cancer has increased more than any other disease over the past 30 years. And while some patients respond well to chemotherapy and radiation treatment, most do not because the cancer becomes resistant to these treatments.

Focusing on cancer stem cells, researchers at Trinity College Dublin have identified an approach that may overcome treatment resistance.

Within tumors are thought to lie cancer stem cells that, just like stem cells, have the ability to multiply indefinitely. Even though they make up a small portion of a tumor, in some patients the cancer stem cells evade the initial rounds of treatment and are responsible for the return of the cancer which is often more aggressive. Currently, there’s no effective way to figure out how well a patient with esophageal cancer will response to treatment.

In the current study published in Oncotarget, the researchers found that a genetic molecule called miR-17 was much less abundant in the esophageal cancer stem cells. In fact, the cancer stem cells with the lowest levels of miR-17, were the most resistant to radiation therapy. The researchers went on to show that adding back miR-17 to the highly resistant cells made them sensitive again to the radiation. Niamh Lynam-Lennon, the study’s first author, explained in a press release that these results could have direct clinical applications:

“Going forward, we could use synthetic miR-17 as an addition to radiotherapy to enhance its effectiveness in patients. This is a real possibility as a number of other synthetic miR-molecules are currently in clinical trials for treating other diseases.”

CIRM-Funded Scientists Make New Progress Toward Engineering a Human Esophagus

Creating tissues and organs from stem cells—often referred to as ‘tissue engineering’—is hard. But new research has discovered that the process may in fact be a little easier than we once thought, at least in some situations.

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Last week, scientists at The Saban Research Institute of Children’s Hospital Los Angeles announced that the esophagus—the tube that transports food, liquid and saliva between the mouth and the stomach—can be grown inside animal models after injecting the right mix of early-stage, or ‘progenitor,’ esophageal cells.

These findings, published in the journal Tissue Engineering Part A, are an important step towards generating tissues and organs that have been damaged due to disease or—in some cases—never existed in the first place.

According to stem cell researcher Tracy Grikscheit, who led the CIRM-funded study, the researchers first implanted a biodegradable ‘scaffold’ into laboratory mice. They then injected human progenitor cells into the mice and watched as they first traveled to the correct location—and then began to grow. The ability to both migrate to the right location and differentiate into the right cell type, without the need for any external coaxing, is crucial if scientists are to successfully engineer such a critical type of tissue.

“Different progenitor cells can find the right ‘partner’ in order to grow into specific esophageal cell types—and without the need for [outside] growth factors,” explained Grikscheit in a news release. “This means that successful tissue engineering of the esophagus is simpler than we previously thought.”

Grikscheit, who is also a pediatric surgeon as Children’s Hospital Los Angeles, was particularly hopeful with how their findings might one day be used to treat children born with portions of the esophagus missing—as well as adults suffering from esophageal cancer, the fastest-growing cancer in the U.S.

“We have demonstrated that a simple and versatile, biodegradable polymer is sufficient for the growth of a tissue-engineered esophagus from human cells. This not only serves as a potential source of tissue, but also a source of knowledge—as there are no other robust models available for studying esophageal stem cell dynamics.”

Want to learn more about tissue engineering? Check out these video highlights from a recent CIRM Workshop on the field.