From Stem Cells to Stomachs: Scientists Generate 3D, Functioning Human Stomach Tissue

The human stomach can be a delicate organ. For example, even the healthiest stomach can be compromised by H. pylori bacteria—a tiny but ruthless pathogen which has shown to be linked to both peptic ulcer disease and stomach cancer.

The best way to study how an H. pylori infection leads to conditions like cancer would be to recreate that exact environment, right down to the stomach itself, in the lab. But that task has proven far more difficult than originally imagined.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

But now, scientists at the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine have successfully grown functional, human stomach tissue in a dish—the first time such a feat has been accomplished.

Further, they were then able to test how human stomach tissue reacts to an invasion by H. pylori—a huge leap forward toward one day developing treatments for potentially deadly stomach disease.

Reporting in today’s issue of the journal Nature, senior author Jim Wells describes his team’s method of turning human pluripotent stem cells into stomach cells, known as gastric cells. Wells explained the importance of their breakthrough in a news release:

“Until this study, no one had generated gastric cells from human pluripotent stem cells. In addition, we discovered how to promote formation of three-dimensional gastric tissue with complex architecture and cellular composition.”

The team called this stomach tissue gastric organoids, a kind of ‘mini-stomach’ that mimicked the major cellular processes of a normal, functioning human stomach. Developing a human model of stomach development—and stomach disease—has long been a goal among scientists and clinicians, as animal models of the stomach did not accurately reflect what would be happening in a human stomach.

In this study, the research team identified the precise series of steps that can turn stem cells into gastric cells. And then they set these steps in motion.

Over the course of a month, the team coaxed the formation of gastric organoids that measured less than 1/10th of one inch in diameter. But even with this small size, the team could view the cellular processes that drive stomach formation—and discover precisely what happens when that process goes awry.

But what most intrigued the researchers, which also included first author University of Cincinnati’s Kyle McCracken, was how quickly an H. pylori infection impacted the health of the stomach tissue.

“Within 24 hours, the bacteria had triggered biochemical changes in the organ,” said McCracken.

According to McCracken, as the H. pylori infection spread from cell to cell, the researchers also recorded the activation of c-Met, a gene known to be linked to stomach cancer—further elucidating the relationship between H. pylori and this form of stomach disease.

Somewhat surprisingly, little was known about how gastric cells play a role in obesity-related diseases, such as type 2 diabetes. But thanks to Wells, McCracken and the entire Cincinnati Children’s research team—we are that much closer to shedding light on this process.

Wells also credits his team’s reliance on years of preliminary data performed in research labs around the world with helping them reach this landmark:

“This milestone would not have been possible if it hadn’t been for previous studies from many other basic researchers on understanding embryonic organ development.”

Disease in a Dish – That’s a Mouthful: Using Human Stem Cells to Find ALS Treatments

Saying “let’s put some shrimp on the barbie” will whet an Australian’s appetite for barbequed prawns but for an American it conjures up an odd image of placing shrimp on a Barbie doll. This sort of word play confusion doesn’t just happen across continents but also between scientists and the public.

Take “disease in a dish” for example. To a stem cell scientist, this phrase right away describes a powerful way to study human disease in the lab using a Nobel Prize winning technique called induced pluripotent stem cells (iPSC). But to a non-scientist it sounds like a scene from some disgusting sci-fi horror cooking show.

Our latest video Disease in a Dish: That’s a Mouthful takes a lighthearted approach to help clear up any head scratching over this phrase. Although it’s injected with humor, the video focuses on a dreadful disease: amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig’s disease, it’s a disorder in which nerve cells that control muscle movement die. There are no effective treatments and it’s always fatal, usually within 3 to 5 years after diagnosis.

To explain disease in a dish, the video summarizes a Science Translation Medicine publication of CIRM-funded research reported by the laboratory of Robert Baloh, M.D., Ph.D., director of Cedars-Sinai’s multidisciplinary ALS Program. In the study, skin cells from patients with an inherited form of ALS were used to create nerve cells in a petri dish that exhibit the same genetic defects found in the neurons of ALS patients. With this disease in a dish, the team identified a possible cause of the disease: the cells overproduce molecules causing a toxic buildup that affects neuron function. The researchers devised a way to block the toxic buildup, which may point to a new therapeutic strategy.

In a press release, Clive Svendsen, Ph.D., a co-author on the publication and director of the Cedars-Sinai Regenerative Medicine Institute had this perspective on the results:

“ALS may be the cruelest, most severe neurological disease, but I believe the stem cell approach used in this collaborative effort holds the key to unlocking the mysteries of this and other devastating disorders.”

The video is the pilot episode of Stem Cells in Your Face, which we hope will be an ongoing informational series that helps explain the latest advances toward stem cell-based therapies.

For more information about CIRM-funded ALS research, visit our ALS fact sheet.

Stem Cells become Tool to Screen for Drugs; Fight Dangerous Heart Infections.

A Stanford study adds a powerful example to our growing list of diseases that have yielded their secrets to iPS-type stem cells grown in a dish. These “disease-in-a-dish” models have become one of the most rapidly growing areas of stem cell science. But this time they did not start with skin from a patient with a genetic disease and see how that genetic defect manifests in cells in a dish. Instead they started with normal tissue and looked at how the resulting cells reacted to viral infection.

They were looking at a nasty heart infection called viral myocarditis, which can begin to cause damage to heart muscle within hours and often leads to death. Existing antiviral drugs have only a modest impact on reducing these infections. So even though there is an urgent need to find better drugs, animal models have not proven very useful and there is no ready supply of human heart tissue for lab study.

To create a ready supply of human heart tissue Joseph Wu’s CIRM-funded team at Stanford started with skin samples from three healthy donors, reprogrammed them into iPS cells and then matured those into heart muscle tissue. Then they took one of the main culprits of this infection, coxsackievirus, and labeled it with a fluorescent marker so they could track its activity in the heart cells.

They were able to verify that the virus infected the cells in a dish just as they do in normal heart tissue. And when they tried treating the cells with four existing antiviral drugs they saw the same modest decrease in the rate of infected cells seen in patients. For one of the drugs that had been shown to cause some heart toxicity, they also saw some damage to the cells in the dish.

They propose that their model can now be used to screen thousands of compounds for potentially more effective and safer drugs. They published their results in Circulation Research July 15.