Lab-grown intestine regenerates gut tissue in dogs

By John Murphy, MDLinx
Published October 9, 2015

Key Takeaways

Scientists have successfully created a lab-made intestine that lays the groundwork for replacement intestine in humans—an innovation could lead to clinical use in patients with short bowel syndrome or intestinal failure.

In a series of experiments, investigators from the Johns Hopkins Children’s Center, in Baltimore, MD, and the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, in Pittsburgh, PA, used intestinal stem cells, which they cultured with cellular and microbial components, and grew them onto a novel 3-D tubular scaffold.

When they implanted the lab-created intestine into the colons of dogs with missing gut lining, the scaffold successfully regenerated gut tissue, the researchers reported. Their study was published online September 23, 2015 in Regenerative Medicine.

“Our experiments show that the architecture and function of our lab-made intestine strikingly resemble those of the healthy human gut, giving us real hope that our model could be used as the backbone for replacement intestine,” said principal investigator David Hackam, MD, PhD, the Johns Hopkins Children’s Center’s surgeon-in-chief, who initiated and conducted most of the work at the University of Pittsburgh.

This investigation combined three components in a specific process: a tube-shaped scaffold, intestinal progenitor cells, and cellular and microbial additions.

The tube-shaped scaffold, designed several years ago in collaboration with researchers at Cornell University, was modeled after the small intestine and made of poly-lactic-glycolic acid (PLGA), a biodegradable copolymer used to make grafts, sutures, surgical sealant films, and other biomedical devices.

The researchers applied intestinal progenitor cells, derived from mouse and human ileum, to the scaffold. To this, they added macrophages and myofibroblasts. The idea, the scientists said, was to create a structure that closely mimics the natural composition of the intestine.

“Intestinal cells do not grow and develop in a vacuum, so we sought to recreate the richness of the human gut,” said Dr. Hackam, who explained that assembling the components was something like making a peanut butter and jelly sandwich. “We took the PB & J approach, adding a layer of stem cells on top of the scaffold, then topping them with a mixture of immune and collagen cells.”

Adding immune and connective cells enhanced the growth and differentiation of intestinal stem cells into various mature cell types critical to the function of a healthy intestine. In comparison, stem cells grown in isolation without the addition these components grew more slowly and failed to differentiate well into multiple cell types.

In another set of experiments, researchers added probiotic bacteria to the newly created intestinal tissue. Doing so further amplified the growth and differentiation of new gut cells, specifically the growth of Paneth cells, which help guard against intestinal infections, Dr. Hackam said.

Researchers then implanted the newly created intestine into the omentum of mice. In a matter of days, the implanted intestine began producing new intestinal stem cells and stimulated the growth of new blood vessels around the implant.

Building on the success of the mice experiments, the investigators then implanted pieces of the newly created intestine—about 1.6 inches in length—into the distal colon of dogs whose intestinal mucosa had been removed.

For two months, the dogs underwent periodic colonoscopies and intestinal biopsies. Within eight weeks, the dogs with implanted intestines had healed completely. By contrast, dogs that didn’t get intestinal implants experienced continued inflammation and scarring.

“Our results move research beyond the proof-of-concept realm,” said study author Stephen Badylak, DVM, PhD, MD, professor of surgery and deputy director of the McGowan Institute for Regenerative Medicine. “These results demonstrate that a mixture of synthetic and natural tissue can spur the formation of new gut cells and function well in living organisms despite the presence of naturally occurring inflammation and microbes found in the living gut.”

Further investigations are needed before the lab-grown intestine can be used in humans, the authors concluded. But if it can restore the intestinal lining using a simple anastomotic technique, “patients may benefit from enhanced mucosal regeneration and potentially avoid the need for a stoma,” they wrote.

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