Heart cells divide again?

One perplexing question in regenerative medicine is why the human heart muscle cells are unable to divide and multiply their numbers. If they could, maybe they'd be able to produce new heart cells to replace those lost after a heart attack. Newts and salamanders can do it, why can't we?



CIRM grantees at the University of California, Los Angeles have found one answer to the question, which could lead to a way of turning the cell's clock back to a time when they could still divide. Robb MacLellan, who was senior author on the work published in the Aug. 8 issue of the Journal of Cell Biology, said that the ability to divide is a trade off. A UCLA press release wrote:

MacLellan believes the reason adult human cardiac myocytes can’t [divide] is quite simple – when the myocytes are in a more primitive state, they are not as good at contracting, which is vital for proper heart function. Because humans are much larger than newts and salamanders, we needed more heart contraction to maintain optimum blood pressure and circulation.

MacLellan suggests that it might be possible to get the heart cells dividing again by blocking the proteins that are halting the cell cycle. The press release had this explanation:

When a heart attack occurs, oxygen is cut off to part of the heart, causing the cardiac myocytes to die and resulting in scar tissue. It’s easy to locate the damaged area of the heart, and if a way could be developed to reprogram a patient’s own myocytes, the protein manipulation system could be injected into the damaged area, reverting the myocytes to their primitive state and replacing the dead muscle with new, living muscle, MacLellan said.



“People have been talking about the regenerative potential of these lower organisms for a long time and why this does not occur in humans” MacLellan said. “This is the first paper that provided a rationale and mechanism for why this happens.”



…



“From my point of view, this is a potential mechanism to regenerate heart muscle without having to harvest or expand stem cells,” MacLellan said. “Each person would be their own source for cells for regeneration.”

MacLellan has two CIRM Basic Biology (Basic Biology I, Basic Biology III) awards to study human heart progenitor cells.



A.A.

Techniques for tracking stem cells necessary for possible therapies

Last week The Scientist carried a story addressing a topic near and dear to the heart of anyone trying to develop a therapy based on transplanting stem cells, whether they are embryonic, adult, or iPS cells: Where do the cells go once they are transplanted?

The problem is this — if you, as a scientist, transplant stem cells near some damage that you are hoping they will repair, you've got to hope those cells actually make it to the damaged tissue. If they make a run for the liver when you are trying to treat the heart, or simply sit in a lump where you implanted them, those cells aren't going to fulfill their mission.

The story quotes CIRM grantee Joseph Wu of Stanford University who has SEED and Basic Biology III Awards to detect stem cells implanted into the heart and to develop stem cell transplantation therapies for hypertrophic cardiomyopathy.

“If you want to understand what happens to these stem cells, it’s important to track the fate of these cells without having to kill the animal,” says Joseph Wu, a cardiologist at Stanford University School of Medicine in Palo Alto, California. Stem cell transplants may settle down, proliferate, and differentiate as desired; they may form dangerous tumors; or they may simply falter and die.

The issue is also one CIRM grantee Paul Knoepfler of the University of California, Davis, touched on in his blog last week, saying:

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

He goes on to discuss some of what's known about the issue using Geron's clinical trial as an example.

In their article, the Scientist discusses a few techniques scientists are using (including some nice images) to address the question of where the cells go. The story includes a technique being used by CIRM grantee Eduardo Marban at Cedars-Sinai Medical Institute, who has a Disease Team Award to develop a therapy for heart disease.

This is the type of research that comes to mind when people who don't follow the science comment on the lack of cures. CIRM is funding a broad range of science, some of which is primarily dedicated developing new therapies, and some of which is working to understand these kinds of basic questions that need to be addressed before those therapies can become widespread.

A.A.

iPS cells reveal stem cell origin of disease

A new Nature paper from CIRM grantees at Stanford University once again shows the value of reprogrammed iPS cells in understanding disease. Scientists can't develop a therapy for a disease if they don't know what it is going wrong. In many cases, iPS cells have provided the first ever way of peering into diseased cells and finding which proteins and genes need fixing.

In this case, the disease in question is dyskeratosis congenita, in which the caps on the ends of chromosomes shorten abnormally and causes a wide variety of symptoms ranging from abnormal skin pigmentation and nail growth to lung scarring, bone marrow failure and cancer. The question has been why people with the same disease can have such dramatically different symptoms, and what to do about those symptoms.

The Stanford group reprogrammed the skin cells of people with the disease into embryonic-like iPS cells. They knew people with the disease made low levels of a protein conglomerate called telomerase, which is responsible for maintaining those chromosomal caps. What they found in those iPS cells is that the more severe a person's disease, the less telomerase their iPS cells made.

A Stanford press release quotes senior author Steven Artandi:

"We were very surprised to find such a clear correlation between the quantity of functional telomerase, the severity of the cellular defect and the severity of the patient's clinical symptoms," said associate professor of medicine Steven Artandi, MD, PhD. "Our work suggests that, in patients with dyskeratosis congenita, tissue stem cells are losing their ability to self-renew throughout the body. This is a new, unifying way to think about this disease, and it has important implications for many other conditions."

Reprogrammed iPS cells can normally divide indefinitely in the lab. The iPS cells made from people with dyskeratosis congenita eventually stopped being able to divide and instead matured into the body's cell types. The researchers think this means the disease symptoms occur when stem cells in the tissues lose their ability to divide indefinitely. With no stem cells in the bone marrow, skin or other organs, the person's body can't repair damage or maintain tissues. That seems to be what causes symptoms of dyskeratosis congenita.

Nature, May 22, 2011
CIRM funding: Steven Artandi (RB2-01497)

The next big thing -- and how to fund it

Gina Kolata had an interesting piece in today’s New York Times about the difficulty of predicting where the next big biomedical breakthrough will come. She, like many people, had predicted big things for gene therapy. She was wrong.

She writes:

But was I right to say advances are unpredictable? Yes and no, scientists say.

“I’ve learned over the years that the best predictor for what will be new and exciting is, ‘Expect the unexpected,’ ” said Dr. Joseph L. Goldstein, a Nobel laureate who is professor and chairman of the department of medical genetics at the University of Texas Southwestern Medical Center in Dallas.

Dr. David Baltimore of CalTech, another Nobel laureate, said, “If you could predict it, it wouldn’t be a breakthrough.”

She goes on to quote Dr. Richard Klausner, a former head of the National Cancer Institute, who says Moore's Law, which refers to the exponential increase in computer processing speed, also applies to biomedical research.

When that happens, Dr. Klausner said, “barriers and unknowns seem to be falling,” and it is pretty much predictable that even more exciting discoveries will be made.

He thinks that's where discoveries relating to stem cell fate are today. In fact, yesterday we wrote about yet another discovery in that area.

CIRM’s Basic Biology Awards are our answer to the problem of trying to fund the next big thing. (Here are recipients of the Basic Biology I and Basic Biology II awards.) The goal is to fund researchers looking into basic questions of how stem cells function, with the idea that the answers might lead to insights that generate new uses for stem cells. Those insights might be in the area of transplantation, but could also reveal new ways of developing drugs or understanding disease or controlling stem cell fate.

Or, the breakthroughs might be in an area that doesn’t yet have a name. Who knows?

A.A.