David Hackam spends much of his work day at the Johns Hopkins Children’s Center removing blackened sections of dead intestine from sick babies. But someday the pediatric surgeon may have a way to restore ravaged intestines—thanks to his work growing the organ in the lab. Starting with stem cells from the small intestines of human infants and mice, Hackam and his colleagues have for the first time grown intestinal linings on gut-shaped scaffolds that could one day treat bowel disorders like necrotizing enterocolitis and Crohn’s disease. They have found that the tissue and scaffolding are not rejected, but instead readily assimilate in lab animals. Most strikingly, the scaffold allowed dogs to heal from damage to the colon lining, restoring healthy bowel function.
The study is a “great breakthrough,” says Hans Clevers, a stem cell biologist at the Hubrecht Institute in Utrecht, the Netherlands, who was not involved in the new research. Clevers was the first to identify stem cells in the intestine, and his lab developed the technique Hackam’s team used to grow intestinal tissue.
The idea of making replacement organs by growing cells on a scaffold is not new; other researchers have done so with bladders and blood vessels. But Hackam’s lab-grown intestine—described last week in Regenerative Medicine—comes closer to the shape and structure of a natural intestine than anything created before. In the past, gut lining has been grown on flat scaffolds or petri dishes, where it tended to curl into little balls with the food-absorbing surface trapped inside. Hackam’s group overcame that with their scaffold, made from a material similar to surgical sutures that can be formed into any desired intestinal size and shape. Hackam’s scaffolds are tube-shaped like a real gut, with tiny projections on the inner surface to help the tissue grow into functional small intestine villi, tiny fingers of tissue that help absorb nutrients. “They can now make sheets of cells that can be clinically managed,” Clevers says. “Surgeons can handle these things and just stick them in.”
To grow the gut lining in the lab, the researchers painted the scaffold with a sticky substance containing collagen, dribbled it with a solution of small intestine stem cells, and then let it incubate for a week. They found that adding connective tissue cells, immune cells, and probiotics—bacteria that help maintain a healthy gut—helped stem cells mature and differentiate.
In one set of experiments, the researchers sewed intestines grown from mouse stem cells into the tissue surrounding the mice’s abdominal organs. The lab-grown intestines developed their own blood supply and normal gut structures, even though they were not connected to the animals’ digestive tract. “Using the mouse's own stem cells, we can actually create something that looks just like the native intestine,” Hackam says. The next step, he says, is “to hook it up.”
First, though, they set out to test the new scaffold in dogs. Because the end of the digestive tract is easier to access than the small intestine, the researchers removed sections of colon lining from dogs and replaced it with pieces of scaffolding. The dogs made a complete recovery: Their gut lining regrew onto the scaffold and functioned normally to absorb water from the colon. Within weeks, the scaffolding dissolved and was replaced with normal connective tissue. “The scaffold was well tolerated and promoted healing by recruiting stem cells,” Hackam says. “[The dogs] had a perfectly normal lining after 8 weeks.”
The technique could help more than just dogs and mice. In the future, scaffolds could be custom-designed for individual human patients to replace a portion of an intestine or the entire organ, Hackam says. This could be game-changing for infants with necrotizing enterocolitis, a condition that destroys intestinal tissue in about 12% of premature babies in the United States. It could also repair the guts of patients with Crohn’s disease, an inflammatory bowel disorder that can have life-threatening complications and that affects more than 500,000 people in the United States. But the lab-grown intestines are still a long way from the clinic, Hackam cautions.
First, the researchers have to test lab-grown small intestines in live animals to see if they can absorb food. The technology itself will also need some tweaking. Mari Sogayar, a molecular biologist at the University of São Paulo in Brazil, points out that the collagen product that helps the stem cells stick to the scaffold is not meant for use in people. In the next experiments, Hackam says, the researchers plan to use a surgical-grade alternative.
“I take care of children who have intestinal deficiencies, eating deficiencies, and they are very much at wits' end,” Hackam says. “I think what we can offer in the scientific community is a path toward something that one day will help a child.”