Zebrafish engineered to have their hearts glow red. Credit: Dr. Juan Carlos Ispizua Belmonte, Salk Institute for Biological Studies.

The small, unassuming zebrafish, which has become a stable in biology labs across the globe, can perform an impressive feat of regeneration--it can withstand losing 20 percent of a ventricle, a chamber of the heart, growing it back within a month. Two new studies published yesterday in Nature show the animals regrow their hearts by triggering cell division of adult heart muscle cells rather than via stem cells. If researchers can elucidate the chemical signaling involved in the process, they may be able to find ways to stimulate heart repair or regeneration in humans. While recent research suggests that human hearts do have a limited capacity to generate new cells, heart muscle tends to form scars after heart attack rather than healthy new tissue.

A regenerating zebrafish heart 14 days after injury. Cardiac muscle is labeled in green, DNA is blue and a marker of cell division is shown in red. Credit: Dr. Juan Carlos Ispizua Belmonte, Salk Institute for Biological Studies.

Researchers in Barcelona and San Diego developed zebrafish whose heart muscle cells glow green. After cutting away 20 percent of the fish's ventricle, researchers found that the new replacement cells also glowed green, suggesting they arose from differentiated adult cells rather than cardiac stem cell. According to ScienceNow,

...Further experiments showed that the cardiomyocytes near the injury site seem to take a step backward in development, detaching from one another and losing their typical shape--presumably to make it possible for them to start dividing again as they replenish the lost tissue.

Credit: Dr. Juan Carlos Ispizua Belmonte, Salk Institute for Biological Studies.

In a second study, researchers from North Carolina engineered heart cells to glow green when they express a protein unique to embryonic heart cells. Injury to an animal's heart triggered the green glow in nearby cells, suggesting they were de-differentiating in preparation for division. Both studies were published in Nature.

According to an article in the New York Times,

Charles Murry, an expert on heart cell biology at the University of Washington in Seattle, said the two reports raised the tantalizing question of why human hearts could not complete the regeneration process. In human hearts, too, Dr. Murry said, the muscle cells dedifferentiate after injury and double up their DNA, a necessary precursor to cell division. But they do not finish the process, for reasons that are so far unknown.

Learning how to overcome that block may not be so easy, in Dr. Murry's view. "It's tempting to say 'Let's do it how nature does it,' " he said, "but we don't know how nature does it. Some of the best molecular biologists in the world have been working on this for a couple of decades and it hasn't cracked yet."

A drug derived from bone marrow cells has failed two late stage clinical trials, representing a major setback for stem cell medicine. The drug, developed by Osiris, a stem cell company based in Maryland, is considered the closest to market of all the stem cell-based products in human testing.

The announcement follows another significant setback for the field. Last month, Geron, an embryonic stem cell company based in California, announced that its clinical trial for spinal cord injury--set to become the first human trial of human embryonic stem cells--was put on hold by the Food and Drug Administration after animal studies showed that the treatment was linked to increased development of small cysts at the injury site.

Osiris's drug, called prochymal, is a preparation of mesenchymal stem cells (MSCs) isolated from the bone marrow of healthy young adult donors. Research in animals suggests that these cells can reduce inflammation and spur tissue healing by stimulating the release of molecular growth factors.

The drug is also being tested in clinical trials for myocardial infarction, chronic obstructive pulmonary disease (COPD) and type 1 diabetes. Osiris halted a late-stage clinical trial of prochymal for Crohn's disease, a form of inflammatory bowel disease, earlier this year because of the high placebo response rate.

According to an article in The New York Times:

Stem cells, particularly in the form of bone marrow transplants, are already used in medicine. Osiris is hoping that Prochymal will become the first stem cell product approved by the Food and Drug Administration and sold as a mass-produced pharmaceutical product.

But the failure in the two trials could make it hard to reach that goal. Both trials tested Prochymal as a treatment for graft-versus-host disease, which occurs when immune cells in donated marrow attack the recipient's organs as foreign tissue.

In one trial, in which Prochymal was used along with steroids, 45 percent of patients responded to Prochymal and steroids compared with 46 percent who had a response to steroid and a placebo.

In a second trial, in which Prochymal was tested in patients who were not benefiting from steroids, 35 percent of those getting the drug had a resolution of graft-versus-host disease for at least 28 days, compared with 30 percent getting the placebo. The difference was not statistically significant.

Osiris said, however, that in the second trial, the drug did provide a statistically meaningful benefit in patients having graft-versus-host disease that specifically affected their livers or their gastrointestinal tracts.

A mouse derived from iPS cells. Credit: Nature

Two groups of researchers from China have independently shown that induced pluripotent stem (iPS) cells--a newly-developed type of stem cell derived from adult cells--can grow into a fully formed mouse. The findings show that these cells are just as flexible in their fate as embryonic stem cells. The findings were published today in the journals Nature and Cell Stem Cell.

iPS cell reprogramming--a technique first developed in Japan in 2006--has generated a great deal of excitement. Unlike embryonic stem cells, iPS cells can be generated without the destruction of a human embryo and thus circumvent the ethical issues that have mired much of stem cell research. While iPS cells have been shown to be capable of developing into many different cell types, they had not been shown to be equal to embryonic stem cells--until today.

The research shows that the new type of stem cells "satisfy the most stringent criteria of embryonic stem cells--the ability to make a mouse entirely from cells in a petri dish," said George Daley of the Harvard Stem Cell Institute and Children's Hospital of Boston to the Associated Press.

According to a news article at Nature.com:

[Researchers] created a 'tetraploid' embryo by fusing two cells of an early-stage fertilized embryo. A tetraploid embryo develops a placenta and other cells necessary for development, but not the embryonic cells that would become the body. It is, in essence, a car without a driver.

When implanted into these embryos, the iPS cells began to steer development. The developing embryo was transferred to a surrogate mother, and 20 days later a mouse was born. It was black, like the mice used to create the iPS cells and unlike the white mice used to create the tetraploid embryo. DNA tests confirmed the mouse, named Xiao Xiao or 'Tiny', had arisen from the iPS cells.

While successful, the process was difficult. In one of the papers, researchers report 22 live births from 624 injected embryos, a success rate of 3.5%.

According to Nature:

The mice seem to have a high death rate, with some dying after just two days, and others displaying physical abnormalities, details of which the team would not reveal. But some of their mice passed one of the most fundamental tests of health: all 12 mice that were mated produced offspring, and the offspring showed no abnormalities. The team says it now has hundreds of second-generation, and more than 100 third-generation, mice. The team found no tumours in the mice, although they have not systematically looked for them.

...

Both groups are now trying to understand what differences between iPS cells and embryonic stem cells might explain the abnormalities, high death rates, low efficiency rates and the fact that most iPS cell lines don't seem to work in making mice. Zeng and Zhou found, for one thing, that timing was important: cells that formed iPS cell colonies quickly -- after 14 days -- were successful, whereas those that formed colonies after 20 or 36 days did not work. Gao suggests that "aberrant reprogramming" might be to blame, at least for the low efficiency rates.

For more on IPS cells, see Medicine's New Toolbox.