Manufacturing a new gut to treat GI diseases

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Brigham and Women's Hospital
Manufacturing a new gut to treat GI diseases Researchers develop way to grow and control maturation of intestinal stem cells, findings pave new ways to treat gastrointestinal disorders Boston, MA – For those living with gastrointestinal disorders, such as ulcers or Crohn's disease, treatment often means quelling uncomfortable symptoms through medications or dietary changes. But what if one day treatment meant doing away with the old gut for a new gut free of inflamed or diseased tissues?

That is where scientists at Brigham and Women's Hospital (BWH) and Massachusetts Institute of Technology (MIT) are hoping their new study findings will lead. In their work, the researchers were able to grow extensive numbers of intestinal stem cells, then coax them to develop into different types of mature intestinal cells.

The study is published online in this month's Nature Methods.

"Being able to produce a large inventory of intestinal stem cells could be incredibly useful for stem cell therapy, where the cells could be delivered to patients to treat diseases such as Crohn's disease and ulcerative colitis," said Jeffrey Karp, PhD, Division of Biomedical Engineering, BWH Department of Medicine, co-senior study author. "These cells could also be useful for pharmaceutical companies to screen and identify new drugs that could regulate diseases from inflammatory bowel disease, to diabetes, to obesity. However, to date there hasn't been a way to expand intestinal stem cell numbers."

In the "crypts" of the human gut are immature adult stem cells that live alongside specialized cells called Paneth cells. The stem cells remain immature as long as they remain in contact with Paneth cells. But the researchers found that when Paneth cells are removed and replaced with two small molecules involved in cell signaling, these molecules could direct the stem cells to develop into pure populations of proliferating stem cells. By introducing other molecules to the mix, the pure cells could further develop into specialized mature intestinal cells.

"This is an opportunity to generate a large number of relevant mature gastrointestinal cell types that was not possible before and enable high-throughput screening using these cell types," said Xiaolei Yin, PhD, Center for Regenerative Therapeutics, BWH Department of Medicine, lead study author.

Moreover, the researchers note that their findings could be potentially applied for in vivo use of small molecule drugs to help regenerate cells to replace damaged gut tissue caused by disease.

"This opens the door to doing all kinds of things, ranging from someday engineering a new gut for patients with intestinal diseases to doing drug screening for safety and efficacy," said Robert Langer, ScD, MIT, co-senior study author.

### This research was supported by the National Institutes of Health (DE013023) and a Harvard Institute of Translational Immunology/HelmsleyTrust Pilot Grant in Crohn's Disease.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in New England and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information and resources, please visit BWH's online newsroom.