Human Umbilical Mesenchymal Stem Cells Decreases Dextran Sulfate Sodium-Induced Colitis in Mice

Ulcerative colitis is one of the Inflammatory Bowel Diseases (IBDs) that features chronic inflammation of the large intestine. This is an autoimmune disease that features constant attacks by the immune system on the intestinal mucosae, and the inner layer of the large intestine undergoes constant damage and healing, which increases the risk of the patient to developing colorectal carcinoma.

Mesenchymal stem cells have the capability to suppress inflammation, which makes them promising tools for treating diseases like ulcerative colitis. Unfortunately, the lack of reproducible techniques for harvesting and expanding MSCs has prevented bone marrow- and umbilical cord blood-derived MSCs from being routinely used in clinical situations.

However, a study that was published in the journal Clinical and Experimental Pharmacology and Physiology has used Wharton’s jelly derived umbilical MSCs (UMSCs) to treat mice in which an experimental form of ulcerative colitis was induced. Dextran sulfate sodium (DSS) induced colitis in mice has many of the pathological features of ulcerative colitis in humans.

When mice treated with DSS were also given Wharton’s jelly derived UMSCs showed significant diminution of the severity of colitis. The structure of the tissue in the colon looked far more normal and the types of molecules produced by inflammation were significantly reduced. In addition, transplantation of UMSCs reduced the permeability of the intestine and also increased the expression of tight junction proteins, which help knit the colonic cells together and maintain the structural integrity of the colon. These results show that the anti-inflammatory properties of UMSCs and their capacity to regulate tight junction proteins ameliorates ulcerative colitis.

Stem Cell Transplant Repairs the Damage that Results from Inflammatory Bowel Disease

A source of stem cells from the digestive tract can repair a type of inflammatory bowel disease when transplanted into mice has been identified by British and Danish scientists.

This work resulted from a collaboration between stem cell scientists at the Wellcome Trust-Medical Research Council/Cambridge Stem Cell Institute at Cambridge University, and the Biotech Research and Innovation Centre (BRIC) at the University of Copenhagen, Denmark. This research paves the way for patient-specific regenerative therapies for inflammatory bowel diseases such as ulcerative colitis.

All tissues in out body probably contain a stem cell population of some sort, and these tissue-specific stem cells are responsible for the lifelong maintenance of these tissues, and, ultimately, organs. Organ-specific stem cells tend to be restricted in their differentiation abilities to the cell types within that organ. Therefore, stem cells from the digestive tract will tend to differentiate into cell types typically found in the digestive tract, and skin-based stem cells will usually form cell types found in the skin.

When this research team examined developing intestinal tissue in mouse fetuses, they discovered a stem cell population that differed from the adult stem cells that have already been described in the gastrointestinal tract. These new-identified cells actively divided and could be grown in the laboratory over a long period of time without terminally differentiating into adult cell types. When exposed to the right conditions, however, these cells could differentiate into mature intestinal tissue.


Could these cells be used to repair a damaged bowel? To address this question, this team transplanted these cells into mice that suffered from a type of inflammatory bowel disease, and within three hours the stem cells has attached to the damaged areas of the mouse intestine. integrated into the intestine, and contributed to the repair of the damaged tissue.

“We found that the cells formed a living plaster (British English for a bandage) over the damaged gut,” said Jim Jensen, a Wellcome Trust researcher and Lundbeck Foundation fellow, who led the study. “They seemed to response to the environment they had been placed in and matured accordingly to repair the damage. One of the risks of stem cell transplants like this is that the cells will continue to expand and form a tumor, but we didn’t see any evidence of that with this immature stem cell population from the gut.”

Because these cells were derived from fetal intestines, Jensen and his team sought to establish a new source of intestinal progenitor cells.  Therefore, Jensen and others isolated cells with similar characteristics from both mice and humans, and  made similar cells similar cells by reprogramming adult human cells in to induced pluripotent stem cells (iPSCs) and growing them in the appropriate conditions.  Because these cells grew into small spheres that consisted of intestinal tissue, they called these cells Fetal Enterospheres (FEnS).

Established cultures of FEnS expressed lower levels of Lgr5 than mature progenitors and grew in the presence of the Wnt antagonist Dkk1 (Dickkopf).  New cultures can be induced to form mature intestinal organoids by exposure to the signaling molecule Wnt3a. Following transplantation in a model for colon injury, FEnS contributed to regeneration of the epithelial lining of the colon by forming epithelial crypt-like structures that expressed region-specific differentiation markers.

“We’ve identified a source of gut stem cells that can be easily expanded in the laboratory, which could have huge implications for treating human inflammatory bowel diseases. The next step will be to see whether the human cells behave in the same way in the mouse transplant system and then we can consider investigating their use in patients,” Jensen said.

Treating Crohn’s Disease Fistulas with Fat Stem Cells

All of us have probably heard of Crohn’s disease or have probably known someone with Crohn’s disease. While the severity of this disease varies from patient to patient, some people with Crohn’s disease simply cannot get a break.

Crohn’s disease is one of a group of diseases known as IBDs or “Inflammatory Bowel Diseases.” IBDs include Crohn;s disease, which can affect either the small or large intestine and rarely the esophagus and mouth, ulcerative colitis, which is restricted to the large intestine, and other rarer types of IBDs known that include Collagenous colitis, Lymphocytic colitis, Ischaemic colitis, Diversion colitis, Behçet’s disease, and Indeterminate colitis.

Crohn’s disease (CD) involves the patient’s immune system attacking the tissues of the gastrointestinal tract, which leads to chronic inflammation within the bowel. While the exact mechanism by which this disease works is still not completely understood and robustly debated, Crohn’s disease was originally thought to be an autoimmune disease in which the immune system recognizes some kind of surface protein in the gastrointestinal tract as foreign and then attacks it. However, genetic studies of CD, linked with clinical and immunological studies have shown that this is not the case. Instead, CD seems to be due to a poor innate immunity so that the bowel has an accumulation of intestinal contents that breach the lining of the gastrointestinal tract, resulting in chronic inflammation. A seminal paper by Daniel Marks and others in the Lancet in 2006 provided hard evidence that this is the case. When Marks and others tested the white blood cells from CD patients and their ability to react to foreign invaders, those cells were sluggish and relatively ineffective. Therefore, Crohn’s seems to be an overactivity of the acquired immunity to make up for poor innate immunity.

Given all that, one of the biggest, most painful consequences of CD are anal fistulas. If those sound painful it’s because they are. A fistula is a connection between to linings in your body that should not normally be connected. In CD patients, the anus and the attached rectum get kicked about by excessive inflammation and tears occur. These tears heal, but the healing can cause connections between linings that previously did not exist. Therefore fecal material not comes out of the body in more than one place. Sounds disgusting? It gets worse. Those areas that leak feces are not subject to extensive pus formation and they must be fixed surgically. But how do you fix something that is constantly inflamed? It’s an ongoing problem in medicine.

Enter stem cells to the rescue, maybe. In Spain, a multicenter clinical study has just been published that shows that fat-derived mesenchymal stem cells might provide a better way to treat these fistulas in CD patients. Mesenchymal stem cells have the ability to suppress inflammation, and for that reason, they are excellent candidates to accelerate healing in cases such as these.

Galindo and his group took 24 CD patients who had at least one draining fistula (yes, some have more than one) and gave them 20 million fat-derived mesenchymal stem cells. These cells were extracted from someone else, which is an important fact, since liposuction procedures on these patients might have added to their already surfeit of inflammation.

For this treatment, the cells were administered directly on the lesion, which is almost certainly important. If the closing of the fistula was incomplete after 12 weeks, then the patients were given another dose of 40 million fat-derived mesenchymal stem cells right on the lesion. All these patients were followed until week 24 after the initial stem cell administration.

The results were very hopeful. There were no major adverse effects six months after the stem cell treatment. This is a result seen over and over with mesenchymal stem cells – they are pretty safe when administered properly. Secondly, full analysis the data showed that at week 24 69.2% of the patients showed a reduction in the number of draining fistulas. Even more remarkably, 56.3% of the patients achieved complete closure of the treated fistula. That is just over half. Also, 30% of the cases showed complete closure of all existing fistulas. These results are exciting when you consider the criteria they used for complete closure: absence of draining pus through its former opening. complete “re-epithelization” of the tissue, which means that the lining of the tissue is healed, looks normal and is properly attached to the proper neighbors, and magnetic resonance image (MRI) scans of the region must look normal. For these patients, the MRI “Score of Severity,” which is a measure of the structural abnormality of the anal region, showed statistically significant reductions at week 12 with a marked reduction at week 24. Folks that’s good news.

Galindo interprets his results cautiously and notes that this is a small study, which is true. He also states that the goal of this study was to ascertain the safety of this technique, and when it comes to safety, this technique is certainly safe. When it comes to efficacy, another larger study is required that specifically examined the efficacy of this technique. Galindo is, of course, quite correct, but this is certainly a very exciting result, and hopefully these cells will get further chances to “strut their therapeutic stuff.”

See de la Portilla F, et al Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial.  Int J Colorectal Dis. 2013 Mar;28(3):313-23. doi: 10.1007/s00384-012-1581-9. Epub 2012 Sep 29.

Adult Stem Cells Isolated From Human Intestines

A laboratory at the University of North Carolina at Chapel Hill has, for the first time, isolated adult stem cells from human intestinal tissue. This achievement should provide a much-needed resource for stem cells researchers to examine the nuances of stem cell biology. Also, these new stem cells should provide stem cell researchers a new tool to treat inflammatory bowel diseases or to mitigate the side effects of chemotherapy and radiation, which often damage the gut.

Scott T. Magness, assistant professor in the departments of physiology at UNC, Chapel Hill, said, “Not having these cells to study has been a significant roadblock to research. Until now, we have not had the technology to isolate and study these stem cells – now we have the tools to start solving many of these problems.”

The study represents a leap forward for a field that for many years has had to resort to conducting experiments with mouse stem cells. While significant progress has been made using mouse models, differences in stem cell biology between mice and humans have kept researchers from investigating new therapeutics for human afflictions.

Adam Grace, a graduate student in Magness’ lab, and one of the first authors of this publication, noted, “While the information we get from mice is good foundational mechanistic data to explain how this tissue works, there are some opportunities that we might not be able to pursue until we do similar experiments with human tissue”

This study from the Magness laboratory was the first in the United States to isolate and grow single intestinal stem cells from mice. Therefore, Magness and his colleagues already had experience with the isolation and manipulation of intestinal stem cells. In their quest to isolate human intestinal stem cells, Magness and his colleagues also procured human small intestinal tissue for their experiments that had been discarded after gastric bypass surgery at UNC.

To develop their technique, Magness and others simply tried to recapitulate the technique they had developed in used to isolate mouse intestines to isolate stem cells from human intestinal stem cells. They used cell surface molecules found on in the membranes of mouse intestinal stem cells. These proteins, CD24 and CD44, were also found on the surfaces of human intestinal stem cells. Therefore, the antibodies that had been used to isolate mouse intestinal stem cells worked quite well to isolate human intestinal stem cells. Magness and his co-workers attached fluorescent tags to the stem cells and then isolated by means of fluorescence-activated cell sorting.

This technique worked so well, that Magness and his colleagues were able to not only isolated human intestinal stem cells, but also distinct types of intestinal stem cells. These two types of intestinal stem cells are either active stem cells or quiescent stem cells that are held in reserve. This is a fascinating finding, since the reserve cells can replenish the stem cell population after radiation, chemotherapy, or injury.

“Now that we have been able to do this, the next step is to carefully characterize these populations to assess their potential, said Magness. He continued: “Can we expand these cells outside the body to potentially provide a cell source for therapy? Can we use these for tissue regeneration? Or to take it to the extreme, can we genetically modify these cells to cure inborn disorders or inflammatory bowel disease? Those are some questions that we are going to explore in the future.”

Certainly more papers are forthcoming on this fascinating and important topic.

Stem Cell Therapy for Inflammatory Bowel Disease

Graca Almeida-Porada is professor of regenerative medicine at Wake Forest University in the Wake Forest Baptist’s Institute for Regenerative Medicine. Dr. Almeida-Porta and her colleagues have identified a special population of stem cells in the bone marrow that can migrate to the intestine and regenerate the intestine. Thus this stem population might provide a treatment for inflammatory bowel diseases or IBDs.

Approximately one million Americans have IBDs, and the main IBDs are ulcerative colitis, which is restricted to the large intestine, and Crohn’s disease, which involves the small and large intestine. These IBDs result from the immune system recognizing some component of the gastrointestinal system as foreign. and the immune system then attacks the gastrointestinal system as though it was a foreign invader. The result is chronic inflammation in the gastrointestinal tract, pain, bloody stools, redness and swelling of the bowel, in some severe cases, rupture of the bowel and death.

There are no cures for IDBs, but several drugs that suppress the immune response against the bowel, such as mesalamine (marketed as Asacol), sulfasalazine (Azulfidine), balsalazide (Colazal) and olsalazine (Dipentum) can reduce inflammation and assuage the symptoms of IBDs. However, there is no treatment to replace the damaged and dead cells in the bowel that result from the inflammation. Even though the bowel does regenerate to some degree, these extra bouts of cell proliferation can increase the patient’s risk of colon cancer. Is there a stem cell treatment to regenerate the bowel?

Research from Almeida-Porada’s laboratory has identified stem cells from umbilical cord blood that can make blood vessels that can also migrate to the intestine and liver (Wood JA, et al., Hepatology. 2012 Sep;56(3):1086-96). Now work in her lab has extended this original observations.

“We’ve identified two populations of human cells that migrate to the intestine – one involved in blood vessel formation and the other that can replenish intestinal cells and modulate inflammation,” said Almeida-Porada. She continued: “Our hope is that a mixture of these cells could be used as an injectable therapy to treat IBD.”

These cells would theoretically contribute cells to the intestine and facilitate and induce tissue healing and recovery. The lining of the intestine has one of the highest cellular turnover rates in the body. Intestinal cell types are being renewed weekly from this pool of intestinal cells that are in an area of the intestine known as the crypt.

In this current study, Almeida-Porada’s team used specific cell surface proteins (cell markers) to identify a stem cell population in human bone marrow that possesses the highest potential to migrate to the intestine and thrive in the intestine. These intestine-bound cells expressed high levels of a protein called ephrin type B, which is typically found on the surfaces of cells involved in tissue repair and wound closure.

Ephrin Protein Structure
Ephrin Protein Structure

When these ephrin type B-enriched bone marrow cells were injected into fetal sheep, the bone marrow-derived cells were able to migrate to the intestine and contribute to the growth and development of the sheep intestine.  Interestingly, these cells took up their positions in the intestinal crypts.

Almeida-Porada comment on her work:  “Previous studies in animals have shown that the transplantation of bone-marrow-derived cells can contribute to the regeneration of the gastrointestinal tract in IBD.  However, only small numbers of cells were successfully transplanted using this method.  Our goal with the current study was to identify populations of cells that naturally migrate to the intestine and have the intrinsic ability to restore tissue health.”

While these two studies show that the cells can migrate to and survive in a healthy intestine, the next step will be to determine whether they can survive in an inflamed intestine, like the type found in IBD patients.  In could be that preconditioning of the cells is required, as in the case of stem cell treatments for the heart after a heart attack.