Patching Up Damaged Guts with Healing Cells

Under the surface of an organ, many different cell types participate in crucial interactions. This means that when an organ suffers damage, fixing it is not as easy as slapping on a Band-Aid. Scientists need a way to regenerate the organ’s complex tissue structure. Induced pluripotent stem cells (iPSCs), undifferentiated cells with the potential to become any adult cell type, may be the key.

Pediatric surgeon and scientist Michael Helmrath and his team at Cincinnati Children’s Hospital have spent over a dozen years developing strategies to turn iPSCs into intestinal tissue. Now, they have found a way to build 3D intestinal organoids that can heal gut damage in rats.¹ In an interview with The Scientist, Helmrath described how these fuzzy balls of tissue deepened his appreciation for the complexity of intestinal development and illuminated a path toward treating gut damage caused by transplant rejection or inflammatory bowel disease.

What makes organoids an appealing way to heal intestinal tissue?

As a pediatric surgeon for patients who have complex gastrointestinal (GI) disorders, families often ask me, “Can you grow my baby's intestine?” In 2010, my colleague James Wells was the first to pattern iPSCs into in vitro organoids—multi-tissue structures recapitulating developmental processes—that mimicked the proximal small bowel.²

That was fascinating, but in vitro models stay at a very early developmental state, so it was not practical to grow the intestinal tissue outside the body and then put it into the gut. Instead, we needed a way to use the iPSC-derived organoid as a cellular therapy that could regenerate, differentiate, and engraft into an existing intestine.

Other cell therapies have been tried in the past, such as enteroids, which are biopsies that are grown into mature intestinal tissue and put back into the patient. Luckily, organoids have two main advantages over enteroids. First, the iPSC-generated tissue has tremendous regeneration and differentiation potential. Second, the tissue is not just one cell type. It is a niche of progenitors that are both endodermal and mesenchymal. That is really the secret sauce.

How do you create and test these organoids?

We add factors in a dish to pattern the iPSCs into endoderm and then into proximal small bowel tissue that grows in a 3D support structure.³ After 28-35 days of maturation, under the microscope you see a fuzzy ball up to a millimeter in diameter. The fuzzy outside is mesenchyme, and the endoderm is on the inside.

To test the organoids, we use a rat model where we damage the bowel pretty extensively. We cannot just put the intact organoid into the animal; when we tried that, it became an isolated piece of bowel that did not integrate with its surroundings. Instead, we fragment the organoid and put the pieces into the animal’s damaged bowel, where the in vivo environment provides stimuli prompting the organoid to expand and differentiate. The organoid responds prolifically, and with the help of some surgical strategies, it engrafts and heals. Every time we open up an animal’s bowel and see human intestine in continuity with the GI tract, it’s exciting.

These experiments opened our eyes. They highlight the fact that in human diseases with ulcers, the underlying defect is likely not an epithelial defect. It is the supporting mesenchyme—the bed to grow the grass that is the epithelium—that usually is not present. Otherwise, the ulcer would have healed. The ability to provide mesenchyme in this model is likely one of the reasons it does so well in comparison to epithelium alone.

What types of human diseases could this approach help treat?

We are proposing to use this in patients who have non-healing ulcers, which can happen in many different patient conditions. One example is exfoliative rejection of small bowel transplant, which can be fatal. Our idea is to generate organoid lines for those patients in advance of the transplant in case of this type of rejection.

In the long run, we are also going to be able to treat damage to the esophagus, stomach, and colon. Because of the exponential expansion of cells, we do not have to transplant a whole organ. We just transplant small amounts of cells, which migrate in the actual organ to proliferate and differentiate into the structures that are damaged. They integrate with existing structures, but do not migrate through the animal or leave the area of damage.

This interview has been condensed and edited for clarity.