Healing the Wounds of Inflammatory Bowel Disease

A University of Chicago team identified a special type of stem cell that heals damaged bowel tissue in mice, a discovery that may have direct application to humans with inflammatory bowel disease. These early findings, made possible with seed funding from the GI Research Foundation, resulted in a recent five-year, $2.5 million grant from the National Institutes of Health to study those cells in humans.

The state-of-the-art isn't enough when it comes to treating Crohn's disease and ulcerative colitis, the two major types of inflammatory bowel diseases (IBDs).

Medication can reduce the inflammation brought on by these conditions, along with the painful symptoms they cause. Surgery, meanwhile, can remove areas of the digestive tract that have been scarred or don't respond to the medical therapies. Current immunotherapies have revolutionized the treatment of these conditions, which are the result of abnormal immune system response. But there are a large number of ongoing unmet needs and gaps in care. For example, the current medical therapies do not address the root cause of the diseases.

Work by the University of Chicago's Dr. Cambrian Liu and funded by the GI Research Foundation might someday offer a new approach to treatment based on regenerative medicine. Dr. Liu and his team recently identified a unique type of skin-like stem cells that induce the healing of wounds in the colons of mice.

These cells travel from what is known as the anal transition zone, adjacent to the colon, to nearby areas that are ulcerated. They then take on new functions and form a thin, healthy layer of tissue over the wounds.

"These skin-type stem cells can make a hybrid structure that's resistant to the disease and partially restores some of the intestine's functions," Dr. Liu said. By better understanding these stem cells, researchers could ultimately develop a new class of treatments for people with IBD. 

"You could use these cells as a Band-Aid. You could cover up areas of bleeding in these patients so that you can tilt the balance back toward healing. In patients that have really severe disease, [it may even be possible to] rebuild a good portion of the lining of the intestine with these stem cells."

Leveraging seed funding from the GI Research Foundation, the team recently received more than $2.5 million from the National Institutes of Health to further study these cells. Through this study, they are imaging and determining the characteristics of the stem cells in humans and determining how they change in order to heal wounds caused by IBD.

"Ultimately, the advantage of this approach would be that we can pull these stem cells from the patients themselves. The ideal workflow would be to pull some from the patient, regenerate them in the lab, and then transplant them back into the patient. You're getting the benefit of rebuilding the organ without running the huge risk of immunological rejection that comes from using foreign tissue, as can happen with organ transplants," Liu said.

This summer, the team received an additional $100,000 from the GI Research Foundation to study other stem cells in the bowel and explore how the function of those cells might generate an improper autoimmune response in people with IBD. Those insights will help doctors determine who is most likely to respond well to current immunotherapies used to treat IBD and how those immunotherapies might interact with stem cell-based wound healing treatments.

"There's a very important push in understanding GI disease, and especially IBD, as a personalized disease. Everyone is a little different…So we ask questions like: In patients that achieve wound healing naturally, what's different about their stem cells? Does their body create an environment that is more conducive to healing? Is the inflammation that drives inflammatory bowel disease a stem cell-driven process?" Liu said.

A new imaging technique is central to answering these questions. Dr. Liu and his team are the first researchers in the world to use this technique in studying regeneration of the bowel and gastrointestinal tract.

They call it ALCHEMIST, short for Analysis of Cleared Human Intestine. It's based on a technique that is used by brain researchers, and it allows the Liu team to get three-dimensional pictures of samples of intestine that have been removed from a mouse or human at the cellular level. 

"The field has struggled with this - linking changes in these organs down to the very level of the cells that make them up when they're impacted by disease," Liu said. 

"Certainly, we have medical imaging technologies like MRI or CAT scans that can generate three-dimensional views of organs. But those are limited in terms of how small they can see in the body. And, often, the processes that drive disease are going to be found in those very small-scale details."

Previously, the state-of-the-art was to cut samples into extremely thin slices and examine those with a microscope. But, using that method, researchers lose the three-dimensional context that is crucial to understanding how cells are behaving. They also introduce unwanted artifacts into the sample when they cut it with a scalpel. 

With ALCHEMIST, however, the Liu team uses carefully selected chemical reagents to wash out the cell membranes - effectively turning the tissue transparent. These membranes scatter the light that is used by a microscope, and they're partially responsible for leaving observers with a fuzzy picture.

Having washed away much of what confounds the image when looking at a large, thick sample, the team uses a confocal microscope to capture a series of two-dimensional images. The microscope captures those images at different depths and blocks any out-of-focus light before it reaches the camera. They then computationally reconstruct those images into a three-dimensional image of the sample.

This technique allows the team to look at the entire mouse colon at once. It also allows them to look at human samples that are about as large as a person's hand. These are exceptionally large samples that are not typically examined at the cellular level. 

"This makes a huge difference. In health, what happens is, normally tissue is very orderly at a microscopic scale. But when disease happens, that order breaks up, and you can't rely on these traditional slices to tell you much about what's happening in the neighborhoods of that disease. You have to have a Google Earth sort of view of that whole process. ALCHEMIST gives us that, and it's been incredibly helpful and informative for our lab," Liu said.

In the case of the stem cell research, "it allowed us to see the entirety of the mouse distal colon during the healing process. And that showed us the skin-like anal stem cells were contributing to wound healing."

About the GI Research Foundation

The GI Research Foundation was founded in 1961 by grateful patients and friends of the late Dr. Joseph B. Kirsner, a pioneer in gastroenterology who devoted his life to medicine, teaching, and patient care. Today, the University of Chicago Medicine's Digestive Diseases Center, which is supported by the foundation, is internationally recognized for research-driven medicine and its team of highly specialized physicians. For more information, see: https://giresearchfoundation.org

About the University of Chicago Digestive Diseases Center

The Digestive Diseases Center at the University of Chicago Medicine is a collaborative, multidisciplinary network of physicians, researchers and allied health professionals who share a legacy of innovation and a common purpose: to improve the lives of patients who suffer from digestive diseases. For more information, see: https://www.uchicagomedicine.org/conditions-services/digestive-diseases

Source: GI Research Foundation

About GastroIntestinal Research Foundation

About the GastroIntestinal Research Foundation

The GI Research Foundation supports work to treat, cure, and prevent digestive diseases with scientists and physicians at the University of Chicago and throughout the United States.

GastroIntestinal Research Foundation
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