Experimental Drug Can Stimulate the Regrowth of Damaged Tissues


Research at Case Western Reserve, in collaboration with scientists from UT Southwestern Medical Center has identified yet another stem cell-activating drug. In animal models, this drug has helped mice regrow damaged liver, colon, and bone marrow tissue. The experimental drug examined in these experiments might open new possibilities for regenerative medicine. If clinical trials show that this drug therapy works in humans, it might save the lives of critically ill people with liver or colon disease or even some cancers.

This study was published in the journal Science. Even this work is exciting, this research is in the early stages and more work is necessary for the drug can be tested in people.

“We are very excited,” said co-author Sanford Markowitz, professor of cancer genetics at Case Western Reserve’s School of Medicine. “We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly,” he added. “The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases.”

This new drug is called SW033291. SW033291 works by inhibiting an enzyme with the formidable name of 15-hydroxyprostaglandin dehydrogenase, which is mercifully shortened to 15-PGDH. This enzyme degrades regulatory molecules called “prostaglandins.” One of these prostaglandins, known as prostaglandin E2, stimulates stem cell growth and differentiation. Inhibition of 15-PGDH increases the concentrations of prostaglandin E2 and stimulates the growth of tissue stem cells, which promotes healing.

prostaglandin_e2

Markowitz and his colleagues first showed that SW033291 inactivated 15-PGDH in a test tube. When they fed the drug to cells, it also inhibited 15-PGDH. Finally, they gave the drug to lab animals and showed that even in a living body, SW033291 inhibited 15-PGDH.

Does the drug augment healing? To determine this, Markowitz and others subjected mice to lethal doses of radiation, followed by a partial bone marrow transplant. Some of the mice were given SW033291 plus the bone marrow transplant while others received only the transplant. The mice that received SW033291 survived, while the others died.

In other studies, mice that had lost large amounts of blood were given SW033291, and mice given SW033291 recovered normal blood counts six days faster than mice that did not get the treatment.

Mice with an inflammatory disease called ulcerative colitis were given SW033291 and the drug “healed virtually all the ulcers in the animals’ colons and prevented colitis symptoms,” said the study’s authors.

“In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.” Additionally, SW033291 produced no adverse side effects.

Researchers who were not involved with the work said the study showed promise, but urged a heavy dose of caution. For example, Dusko Illic, a stem cell expert at Kings College London, said: “The drug seems to be too good to be true. We would have to be sure that nothing else was wrong with any organ in the body,” because if there were cancer cells present, the treatment would likely cause tumor cells to grow along with other tissue.

However, Ilaria Bellantuono, an expert in stem cell science and skeletal ageing at the University of Sheffield, said a key part of the drug’s promise could be in helping cancer patients, if it is proven safe. The “treatment has the potential of boosting patents’ resilience and improving their response to cancer treatment,” said Bellantuono. “This study is a proof of concept in mice and more experimental work is needed to verify the long-term safety of such an approach but it surely shows promise.”

The author of this study said that the first people to receive the experimental treatment in clinical trials would likely be patients who are receiving bone marrow transplants, have ulcerative colitis, or are undergoing liver surgery.

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.

Fordham_CellStemCell_GraphicalAbstract

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.

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.