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Reprogramming stem cells to heal intestinal mucosa in IBD: fact or fiction?

Dr Cambrian Liu, University of Chicago, IL, USA
Dr Cambrian Liu is a research assistant professor at the University of Chicago (IL, USA) who conducts research in the area of stem cell biology. His research team evaluates how regenerative medicine could be applied to treat various kinds of human diseases. Dr Liu’s focus is primarily on inflammatory bowel disease and diseases of the intestines. Medicom Medical Publishers interviewed him to learn more.
What is the unmet need in this disease area and how could regenerative medicine offer a band-aid?

Inflammatory bowel disease (IBD) affects over 2 million individuals in the United States,” started Dr Liu. “Usually these patients are treated with immunomodulatory drugs or anti-inflammatory agents. Although many effective immune-modulating medications have been developed in recent years, many patients don't respond initially or end up losing their response over time. Therefore, the gold standard of full microscopic healing of the intestinal mucosal layer cannot be achieved in a substantial proportion of patients. The main goal of regenerative medicine in these diseases is to try to help this process along by directly healing that mucosal lining.”
Could you explain what regenerative medicine can and can't do? 

“Regenerative medicine is an umbrella term for two major concepts,” Dr Liu replied. “One is to harness the body's inherent potential for healing. For example, stem cells that are resident within our adult organs may be used for their ability to regenerate. Secondly, it comprises synthetic or bio-derived mechanisms of healing. This is where bioengineering comes into play. Thus, there is a natural approach and a more synthetic approach, but they are both targeted towards healing and regeneration. Regenerative medicine in IBD aims to restore the epithelial layer, the microbiome, as well as the immune homeostasis that is present within a healthy individual. A good number of longitudinal studies show that patients who can achieve mucosal healing actually do a lot better. We therefore think this is a strong and increasingly validated therapeutic target.”
Could you tell us what your lab does exactly?

“My lab is focused on studying the basic biology of how the regenerative process works within the colon,” said Dr Liu. “Our primary method of study is through mouse and preclinical models of intestinal inflammation and IBD. In addition, the University of Chicago has a major IBD centre where they see many IBD patients every year. We are able to work with human tissue and study the disease process, for example, in biopsies and in surgical tissue that we obtain from resections. My lab's focus is on stem cells and determining which populations of stem cells might be driving the healing process. It was always thought that the stem cells within the intestinal crypts are the stem cells that are driving the regenerative process. However, in the last 10 years, there has been a lot of evidence accumulating from mouse injury models in both the colon and the small intestine that suggests that stem cells that can heal tissue can come from multiple sources outside of the crypt.”

“One thing that we're trying to do in the lab is to figure out if there are alternative populations of stem cells that could be activated. For example, in mouse models of injury and inflammation, a lot of these crypt-based stem cells either change fate or become deactivated during injury, which enables another population of stem cells to be activated. Multiple groups have discovered that, during radiation injury, the cells at the top of the villus or near the top of the villus can reprogram back to stem cells. Moreover, my lab discovered that a neighbouring stem cell population of a neighbouring organ, the anus, can move into the colon and form a rudimentary band-aid or healing layer of cells over the colonic epithelial surface.”

Dr Liu continued to explain that these findings fall under the broad umbrella term of ‘cellular plasticity’: “This is going to be a major concept in how we think about regenerative medicine in the future. By relying on cellular plasticity, you can recruit cells of a different origin. Thus, they might have a different embryological origin, but we could engineer restoration of the cell function and, at the same time, confer some resistance to the disease. In addition, IBD can be very specific in terms of what types of organs and cells it attacks. It prefers to target a columnar lining, sometimes an ileal lining, sometimes a colonic lining; which can be very patient-specific. But if we use a different cell type and rely on its ability to convert to another cell type, we might be able to get around some of those limitations.”
Is there hope that this approach will result in longer-term responses? 

“Going back to my earlier example, the skin cells from the anus form what we call squamous neo-epithelium in the colon. The findings from our mouse experiments suggest that it persists for the rest of their lives,” clarified Dr Liu. “Interestingly, when the skin cells move into the colon they are able to adopt more colonic properties. Skin tissue is typically flat and multi-layered. If these cells move into the colon, they form crypt-like structures. They're however not columnar or single-layered. So these cells look like crypts but they're filled with cells instead of being ‘hollow’. Nonetheless, this is evidence of the plasticity that is being activated in these sort of cells. In addition, after these cells have entered the colon, they confer resistance to inflammation to the part that they've healed.”
Do you think that we're going to be able to use this as a supplement to biological therapies for IBD?

“That needs further study,” according to Dr Liu. “One of the main reasons we were able to get a National Institutes of Health (NIH) grant was to study this in more detail. We are growing organoids from skin tissue and we have been able to expand them massively in culture. Currently, we’re conducting experiments to see if we can engraft them to make a band-aid in patients that have severe disease or ulcerations that persist for a long time. Once we have it in culture, we could do some genetic engineering to fix certain defects or imbue them with properties that might partially restore that colonic function. That’s the most positive scenario,” added Dr Liu. “I don't think this is a therapy that will be used on its own. It has to be complemented with anti-inflammatory agents. As a metaphor, imagine a giant forest fire. We need the anti-inflammatory agents to put out the fire and then we need stem cells from one source or another to help the trees grow back.”
Are there any harmful long-term effects?

“Another thing we are testing is whether these cells remain benign in the long term,” answered Dr Liu. “This process has a lot of overlap with how certain metaplasia arise in the body. The most famous metaplasia in the gastrointestinal tract is probably Barrett's metaplasia. It is thought of as a precursor lesion leading to oesophageal cancer. We’re investigating if our process is truly benign. As of yet, we haven't seen cancer arise from our mouse models, but we are conducting more directed tests to make sure that we can avoid cancer. We use techniques to accelerate that process, which is needed because mice have a short lifespan. Both colon and skin-targeted cancer models are used in which we can test the overall susceptibility of these metaplastic-type wound healing phenomena within that model. In addition, we can target certain mutations, such as adenomatous polyposis coli (APC) or other squamous type cancer mutations to see what the susceptibility is. Finally, I would like to encourage everyone to support research into regenerative medicine and basic research. I think we could make great headways in human disease by investing in this essential type of research.”

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