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.

Stem Cells Derived From Amniotic Tissues Have Immunosuppressive Properties


Ever since they were first isolated, amnion-based stem cells have been considered promising candidates for cell therapies because of their ease of access, plasticity, and absence of ethical issues in their derivation and use. However, a Japanese research team has discovered that stem cells derived from human female amnion also have the ability to suppress the inappropriate activation of the immune system and that there are straight-forward ways to enhance their immunosuppressive potential.

The amniotic membrane is a three-layered structure that surrounds the baby and suspends it in amniotic fluid. Amniotic fluid acts as a protective shock-absorber, a lubricant and an important physiological player in the life of the embryo and fetus. Because the fetus is a privileged entity that escapes attack from the mother’s immune system, researchers have been very interested in determining the immunological properties of the amnion cells.

“The human amniotic membrane contains both epithelial cells and mesenchymal cells,” said study co-author Dr. Toshio Nikaido, Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences at the University of Toyama. “Both kinds of cells have proliferation and differentiation characteristics, making the amniotic membrane a promising and attractive source for amnion-derived cells for transplantation in regenerative medicine. It is clear that these cells have promise, although the mechanism of their immune modulation remains to be elucidated.”

In this study by Nikaido and his coworkers, amnion-derived cells inhibited natural killer cell activity and induced white blood cell activation. Nikaido reported that he and his colleagues saw the amnion-derived cells increase production of a molecule called interleukin-10 (IL-10).

“We consider that IL-10 was involved in the function of amnion-derived cells toward NK cells,” explained Dr. Nikaido. “The immunomodulation of amnion-derived cells is a complicated procedure involving many factors, among which IL-10 and prostaglandin E2 (PGE2) play important roles.”

Molecules called “prostaglandins,” such as PGE2, mediate inflammation, smooth muscle activity, blood flow, and many other physiological process. In particular, PGE2 exerts important effects during labor and stimulates osteoblasts (bone-making cells) to release factors that stimulate bone resorption by osteoclasts. PGE2 also suppresses T cell receptor signaling and may play a role in the resolution of inflammation.

When Nikaido and others used antibodies against PGE2 and IL-10, they removed the immunosuppressive effects of the amnion-derived cells on natural killer cells. These data imply that these two factors contribute to the immunosuppressive abilities of amnion-derived cells.

“Soluble factors IL-10 and PGE2 produced by amnion-derived cells may suppress allogenic, or ‘other’ related immune responses,” concluded Dr. Nikaido. “Our findings support the hypothesis that these cells have potential therapeutic use. However, further study is needed to identify the detailed mechanisms responsible for their immodulatory effects. Amnion-derived cells must be transplanted into mouse models for further in vivo analysis of their immunosuppressive activity or anti-inflammatory effects.”

Given the levels of autoimmune diseases on the developed world, these results could be good news for patients who suffer from diseases like Crohn’s disease, systemic lupus erythematosus, or rheumatoid arthritis. While more work is needed, amnion-based cells certainly show promise as immunosuppressive agents.

The study will be published in a future issue of Cell Transplantation.

Taiwanese Group Identifies Stem Cell-Based Drug to Rejuvenate Aged Hearts


A southern Taiwan-based National Cheng Kung University research team led by Patrick Ching-Ho Hsieh has discovered that a molecule called prostaglandin E2 can regenerate aged hearts in rodents.

This discovery provides a useful new perspective on heart regeneration and presents an effective option for heart disease patients other than heart transplant.

According to Hsieh, congestive heart disease and other cardiovascular diseases are a leading cause of morbidity and mortality throughout the world. There are some six million patients with congestive heart failure in the US alone and some 400,000 in Taiwan. Despite intensive drug, surgical and other medical interventions, 80 percent of all heart patients die within 8 years of diagnosis.

Even though several experiments and clinical trials have established that heart regeneration can take place, the means by which the heart regenerates is still not completely clear, and there are also no drugs to stimulate heart regeneration by the resident stem cell population in the heart.

Now, after seven years of hard work, Hsieh’s team has identified the critical time period and the essential player that directs heart repair.

Hsieh and his colleagues used genetically engineered mice that Hsieh had developed as a postdoctoral research fellow at Harvard Medical School. By using this transgenic mouse strain, Hsieh and others showed that the self-repair process of the heart begins 7 days after injury and peaks at 10 days after injury.

The “director” of this self-repair process is the molecule PGE2. PGE2 regulates heart-specific stem cell activities.

PGE2

“More importantly, both young and old mice have significant improvements for cardiac remodeling if you treat both of them [with] PGE2,” said Hsieh.

Hsieh’s team also established that PGE2 decreases expression of a gene associated with aging, TGF-beta1. PGE2 also rejuvenates the micro-environment of the aged cells, according to Hsieh.

Fate Therapeutics Clinical Trial with FT1050 Improves Stem Cell Engraftment In Umbilical Cord Blood Transplant Recipients


Patients who receive umbilical stem cell treatments after bone marrow-ablating cancer treatments usually have to wait for the cells the “engraft” or proliferate and fill the bone marrow. During this engraftment time, these patients are prone to life-threatening infections, since their immune systems are effectively wiped out. However, a natural compound called FT1050 (marketed as Prohema) might improve the ability of stem cells from umbilical cord blood to engraft in patients. A phase I clinical trial led by Dana-Farber Cancer Institute scientists provides genuine hope that this compound might decrease the engraftment time for umbilical cord stems cells.

FT-1050 (16,16-dimethyl Prostaglandin E2) is the first drug candidate from Fate Therapeutics’ platform of Stem Cell Modulators (SCMs). SCMs are small molecules that influence adult stem cells. By treating stem cell patients with SCMs, physicians hope to guide stem cells treatments toward desired outcomes, and these can include cell regeneration, healing or blocking cancer growth. In the case of blood cell-making stem cells (also known as “hematopoietic stem cells” or HSCs), FT1050 can mediate their ability to home to the bone marrow and eventually repopulate the patient’s blood and immune system. Because FT-1050 seems to affect fundamental pathways present in all blood cell-making stem cells, it could improve the efficiency and success of treatments with stem cells from any source, including from bone marrow, peripheral blood, and umbilical cord blood.

This clinical trial involved 12 patients who underwent reduced-intensity chemotherapy and then received a transplant of cord blood stem cells that had been treated with FT1050. FT1050-treated blood-forming stem cells might solve a long-standing problem with umbilical cord transplants – a relatively small number of stem cells are infused during such procedures, and therefore, they often take longer to engraft (or take root) in patients than do the more numerous stem cells involved in transplants from adult donors. These delays during engraftment can leave patients susceptible to dangerous infections and other complications.

Trial leader Corey Cutler, MD, MPH, of Dana-Farber and Brigham and Women’s Hospital put it this way: “There is a significant need to improve the speed and quality of engraftment of cord-derived stem cells. FT1050 has shown the ability in preclinical research to activate hematopoietic [blood-forming] stem cells so they engraft more quickly and with a higher degree of success.”

Umbilical cord stem cell transplants are an excellent option for patients who do not have a closely-matched adult donor. Since the current pool of potential donors is smaller for non-Caucasians than for Caucasians, members of ethnic minorities tend to receive transplants from cord blood at a higher rate than Caucasians.

The goal of this phase I trial was to assess the safety of FT1050-treated cord blood cells in adult patients who receive umbilical cord blood stem cell transplants. Additionally, this trial determined if the treated cells show accelerated engraftment. In the 12 patients who participated in the trial, engraftment occurred approximately three to four days faster than normal. Also the patient’s levels of particular types of white blood cells (neutrophils) returned to normal in the patients after a median of 17.5 days, which is similar to the rate in standard stem cell transplants. Side effects of the FT1050-treated cord blood cells were minimal, and in none of the study patients did the stem cells fail to engraft.

The phase I trial was sponsored by Fate Therapeutics, Inc., of San Diego, Calif., which is developing ProHema, a biologic product that consists of blood cell-making stem cells treated with FT1050 for patients who require a stem cell transplant. FT1050 was identified by Leonard Zon, MD, a hematologist and director of the Stem Cell Program at Children’s Hospital Boston, who used a chemical screens that was conducted in zebrafish. FT1050 is the first potential therapeutic derived from a zebrafish model to make it to clinical trials.

“We’re encouraged by the results of this study for patients receiving umbilical cord stem cell transplants after reduced-intensity chemotherapy treatment,” Cutler says. “Further studies are planned to test FT1050-treated hematopoietic stem cells in a larger group of these patients.”