Mini esophagus grown from stem cells could yield treatments for GI diseases

In a first, researchers from Cincinnati Children’s have grown esophageal organoids entirely from stem cells. Their work is just one step in a quest to bioengineer the entire human gastrointestinal system and come up with regenerative—and potentially curative—treatments for GI diseases. 

The team, from Cincinnati Children’s Center for Stem Cell and Organoid Medicine (CuSTOM), is working on new ways to study birth defects and diseases that affect the GI tract. The team members, along with colleagues from other institutions, have already engineered human intestines, stomach, colon and liver tissue from pluripotent stem cells, but this is the first time they’ve done so with esophageal tissue. 

The fully formed organoids grew to lengths between 300 and 800 micrometers—or one-hundredth and three hundredths of an inch—in about two months. Tests showed that the bioengineered tissue was similar to human esophageal tissue from patient biopsies. The team's future projects will focus on how the organoids can be advanced for therapeutic use, including to study the progression of specific diseases and congenital defects that affect the esophagus. 

To create their mini esophagi, the team focused on the Sox2 gene and its associated protein, which, if disrupted, can lead to esophageal conditions. Using Sox2 as a starting point, they used frogs, mice and human tissue to pinpoint other genes and pathways that Sox2 plays a role in during esophagus formation. 

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The researchers found that Sox2 blocks certain genetic pathways that cause cells to become respiratory rather than esophageal. They also tried deleting the gene in mice during esophageal formation, which led to esophageal agenesis, a condition in which the esophagus does not connect to the stomach and instead ends in a pouch. Their findings appear in the journal Cell Stem Cell.

"Disorders of the esophagus and trachea are prevalent enough in people that organoid models of human esophagus could be greatly beneficial," said Jim Wells, Ph.D., chief scientific officer at CuSTOM and study lead investigator, in a statement. "In addition to being a new model to study birth defects like esophageal atresia, the organoids can be used to study diseases like eosinophilic esophagitis and Barrett's metaplasia, or to bioengineer genetically matched esophageal tissue for individual patients." 

Infants with esophageal atresia are born with an esophagus that grows in two separate segments. It is usually repaired with surgery, though the FDA approved a noninvasive device from Cook Medical last year that uses a magnet to pull the ends of the esophagus together. However, the device cannot be used in infants whose esophageal segments are more than 4 centimeters apart and could result in narrowing of the esophagus—which can also happen with surgical repair—that needs another procedure. 

Atresia is just one example of a GI condition that needs better treatments, which can arise from a better understanding of their underlying genetic and biochemical mechanisms, according to the statement. Creating “robust, functional, genetically matched models of human esophageal tissue” from a patient’s own cells would be one way to get there, the researchers said.