A microscope image shows the engineered human stomach tissues from the corpus/fundus region.
Image credit: Cincinnati Children’s
Stomach-related diseases are common, affecting millions of people. An estimated 25 percent of individuals in the United States are affected by gastrointestinal disorders.
Globally, gastric cancer is the third leading cause of cancer-related deaths.
To trial new drugs and get a better understanding of gastric disease mechanisms, it is vital to have a reliable model of the working human stomach.
Although there are a number of animal models for human gastrointestinal conditions, they can be time-consuming and complicated to use.
Principal investigator Jim Wells, Ph.D., director of the Pluripotent Stem Cell Facility at Cincinnati Children’s, has made it his mission to develop reliable, consistent models of the organs involved in digestion – specifically, the intestines, stomach, pancreas, and esophagus.
His team has designed ways to use pluripotent stem cells to grow organs. Pluripotent stem cells are undifferentiated – in other words, they have the ability to develop into any cell type in the body.
Two years ago, Wells and his team learned how to use pluripotent stem cells to generate a part of the stomach responsible for producing hormones. This region is called the antrum.
Growing a new section of stomach
This week, a report published in the journal Nature describes how the team recently designed a method to grow the stomach’s corpus/fundus region. This is the uppermost section of the stomach, near to the cardiac sphincter where the organ is attached to the esophagus.
“Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it’s possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments.”
Jim Wells, Ph.D.
This discovery is the latest in a long line of studies from Wells’ laboratory to utilize pluripotent stem cells. They specialize in growing organoids, which are simplified versions of human organs that show realistic anatomy, albeit on a much smaller scale.
For example, they successfully engineered human intestine with an enteric nervous system, which was able to absorb nutrients and carry out peristalsis (the contractions that move food along the intestine).
Their new procedure guides pluripotent stem cells through natural developmental stages, turning them into human fundus organoids in just 6 weeks.
The challenges of growing a new organ type
One of the early problems that Wells and his team encountered was the minimal information available on the embryology of the stomach – no one knows exactly how it develops. As Wells explains: “We couldn’t engineer human stomach tissue in a petri dish until we first identified how the stomach normally forms in the embryo.”
Initially, the team had to delve into the genetics involved in development of mice embryos.
This early work showed that the WNT/β-catenin genetic pathway was particularly important in the development of the corpus/fundus region. Using this discovery, they manipulated the WNT/β-catenin pathway in pluripotent stem cells in the laboratory, thereby triggering the formation of human fundus organoids.
In addition to the WNT/β-catenin pathway, the team also needed to replicate other molecular signals to drive the formation of specific cell types that naturally occur within the corpus/fundus region. These specific cell types include chief cells, which are responsible for producing pepsin (an enzyme that breaks down proteins), and parietal cells, which produce hydrochloric acid and intrinsic factor (important for the absorption of B-12).
The team will now use their new model to start investigating human diseases by transplanting them into mice models. For instance, they plan to observe how the fundus organoids respond to Helicobacter pylori bacteria – the cause of stomach ulcers and chronic gastritis, and a significant risk factor for the development of stomach cancer.
Additionally, now that the team has access to both a stomach and intestine model, they hope to study how nutrients are absorbed, how the body controls digestion, and a range of gut disorders.
As technology advances and the resultant organoids become ever more naturalistic, research into gastrointestinal conditions will become easier, quicker, and more productive.