Hope for treating heart disease with stem cells?

It's a big day for announcing prizes to CIRM grantee, and a good week for stem cells in heart disease. CIRM scholar Li Qian from The Gladstone Institutes won the Louis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators from the American Heart Association (AHA). Hers was one of several announcements this week regarding the potential treatments for heart damage after heart attack.

According to a press release from The Gladstone Institutes:

"Dr. Qian received the prize for her findings that non-muscle cells that normally form the architectural support for the heart can be reprogrammed into beating heart muscle cells. This reprogramming may allow scientists to transform non-beating scar tissue resulting from heart disease—and which was previously considered irreparable—into beating tissue again."

Qian is carrying out her work in the lab of CIRM grantee Deepak Srivastava, who last year published work in which he and his colleagues converted mouse heart support cells called fibroblasts into beating heart cells in a laboratory dish (read our blog about that work here). For Qian's work, which was presented at the AHA meeting in Orlando, she and Srivastava carried out the same feat in a living mouse. The team delivered factors directly into the hearts of mice with induced heart attacks (you can read the abstract for that work here). Those injections seemed to have induced support cells to convert into heart muscle cells, and three months later the mice had less heart dysfunction than their labmates who hadn't received the injections.

Of course, mice aren't humans and three months isn't long enough to know if the benefits of the injections will last.

This award comes during what has been a big week for stem cells in heart disease. For many years now, research groups have been testing stem cells isolated from the bone marrow to see if they can effectively treat damage from heart attacks. Results had been ambiguous. Researchers saw some improvement, but it seemed to be short-lived in most studies.

In studies published earlier this week, a group from Louisville and a group of CIRM grantees from Cedars-Sinai both published results suggesting that stem cells isolated from the heart could produce improvements that last up to a year.

ABC News spoke to one of the patients who participated in the University of Louisville trial:

Mike Jones, the very first patient to receive the treatment in July 2009, said it not only gave him more years to live, but a better quality of life during those years.

"Now I can do more with my grandkids," said Jones, 68, who lives in Louisville. "I pitched softballs with my granddaughter for probably 15 minutes today. I got a little bit winded at the end, but that's something that before the stem cells would have been just impossible."

These studies involved small numbers of people and the results need to be confirmed in much larger trials. Still, those of us with heart disease in the family will be watching to see how the cells fare in the larger trials. My own grandfather, unlike Jones, would not have been able to pitch softballs after his heart attack.

A.A.

CIRM grantees at Gladstone Institute receive $5 million to expand stem cell program

The Gladstone Institutes in San Francisco are set to expand their stem cell research program with a $5 million gift from the Roddenberry Foundation.

The independent Institute, which is associated with the University of California, San Francisco, has received $24 million in funding from CIRM (you can see a complete list of those awards here). The 14 awards fund training new stem cell scientists, creating a lab facility where Gladstone scientists can share stem cell resources and awards to aid in creating reprogrammed stem cells (known as iPS cells) and treat cardiovascular diseases and HIV/AIDS, among others.

The Roddenberry gift will expand these existing areas of expertise among Gladstone scientists by creating the Roddenberry Center for Stem Cell Biology and Medicine - named after Gene Roddenberry, who created "Star Trek".

A story by Erin Allday at the San Francisco Chronicle quotes Rod Roddenberry, Gene Roddenberry's son:

"We don't fool ourselves into thinking we're going to cure Alzheimer's or heart disease overnight, but if they tell us they are breaking ground and moving forward, we definitely want to help them do it."

"It was amazing to go up to Gladstone and look through a microscope and see a sheet of beating heart cells, and know they came from skin cells," Roddenberry said. "Walking around the institute, we met scientists who were passionate and excited by what they were doing. And as corny as it sounds, a lot of them believed in the 'Star Trek' future, a beautiful future."

Allday also spoke with CIRM President Alan Trouson about the Gladstone Institutes:

"Gladstone is small, but it's incredibly effective, and it's ranked very high by scientists around this country as one of the best institutes."

A press release from the Gladstone Institutes about the gift quotes Deepak Srivastava, who directs both stem cell and cardiovascular research at Gladstone:

“Today's biggest challenge for solving disease is getting the investments required to transform our basic-science discoveries into health solutions that can alleviate human suffering.”

Investments like those from CIRM and now the Roddenberry Foundation should help accelerate the translation of basic discoveries by Gladstone scientists into real therapies. This video discusses work by Gladstone scientist Bruce Conklin, who is developing a stem cell method of screening drugs to treat a form of heart disease:



A.A.

Heart, heal theyself

A group of researchers from University College London made a splash this week with their work prodding heart muscle to repair itself. This is big news, given both the number of people who have heart attacks (more than 1 million per year in the US) and the number of stem cell scientists working to regenerate the damage (23 awards worth $46 million from CIRM).

The big problem has been this: The heart appears to have some stem-like cells, but in adults they don't do much. They certainly aren't able to repair damage after a heart attack. When the heart is developing, however, those cells are the major source of new heart muscle. So, what gives? Why can't those cells perform in adults the way they do during development?

A story by Mitch Leslie in ScienceNOW has this to say about the UCL work:

To recapture the cells' youthful vigor, the researchers injected mice with thymosin β4, a compound already undergoing clinical trials as a heart attack treatment because it helps cardiomyocytes survive and spurs the growth of new blood vessels. The researchers then mimicked a heart attack in the animals by tying off one of the arteries that deliver blood to the heart, injuring part of the muscle.

Unlike control mice that didn't appear to fashion any new cardiomyocytes, animals dosed with thymosin β4 made some of the cells, the team reports online today in Nature. The cells infiltrated the damaged zone left by the simulated heart attack and meshed with other cardiomyocytes physically and electrically, allowing them to beat. They also seemed to prevent some of the damage that can result from a heart attack. Magnetic resonance imaging scans showed that the hearts of mice that had received thymosin β4 had smaller scars and were able to pump more blood with each contraction than were the hearts of untreated rodents.

The news is good, but thymosin β4 wasn't all that efficient. The group is hoping to find other compounds that can more effectively prod progenitors into action.

This work is interesting, too, because it shows the interplay between stem cell science and traditional drug-based medicine. Transplantation therapies are what grab the stem cell headlines. But studying how stem cells normally function can also lead to the development of new drugs, such as ones that could help the heart heal itself.

The ScienceNOW story quotes CIRM grantee Deepak Srivastava, who made headlines last year when he was able to directly transform support cells in the heart into heart muscle — a trick he'd like to replicated not in a lab dish but in an actual heart.

The study "provides strong evidence that there is a population of cells from the epicardium that can turn into new muscle," Srivastava says. "The real question is how robust is the process [of cell transformation] and how can it be improved." He recommends that researchers also investigate whether the cells can rebuild cardiac muscle during heart failure, a condition that afflicts some 5 million U.S residents and causes the organ to progressively weaken.

A.A.

CIRM grantees directly create neuronal stem cells for research and therapies

CIRM grantees at the Scripps Research Institute, University of California, San Diego and Sanford-Burnham Research Institute have taken an intriguing step toward producing neural progenitor cells for research or therapies. The team, led by Sheng Ding who has recently moved to the Gladstone Institutes in San Francisco, started with mouse skin cells and converted them directly to an early stage of neural cell. The work was published in the April 26 online issue of Proceedings of the National Academy of Sciences.

This work falls somewhere between two other pieces of research starting with skin cells. Since 2006 it has been possible to convert mouse skin cells into reprogrammed iPS cells that are similar to embryonic stem cells in their ability to create all cell types. Scientists could then mature those cells into whatever cell type they are interested in studying.

Over the past year, other groups have started with skin and converted those cells directly to neurons or heart cells.

Ding and his colleagues fall somewhere in the middle, sidestepping some issues with both direct reprogramming and generating iPS cells.

• Converting skin directly into neurons has the major limitation that neurons can't divide. The number of neuronal cells available for research or therapies is limited by the number of starting skin cells.
• Going all the way back to iPS cells has limitations of its own. The cells multiply in a lab dish to create as many cells as a scientist might need for therapies or research uses, but maturing those cells into the appropriate cell type can be an arduous task any traces of the original iPS cells could lead to tumors.

Converting skin to these neural precursors avoids both problems. Those neural cells are already pushed down the pathway to become neurons, and they can multiply. The researchers also showed that the cells can integrate into a mouse brain without developing tumors.
In a press release from the Gladstone Institutes, Ding says:

“These cells are not ready yet for transplantation,” Dr. Ding said. “But this work removes some of the major technical hurdles to using embryonic stem cells and iPS cells to create transplant-ready cells for a host of diseases.”

That's all good, but the work is a long way from ending the need for iPS cells. First, it's in mice. There's no evidence yet that the protocol will work with human cells. Also, the resulting neural progenitors can only divide a few times, so they aren't an unlimited source of cells.

Those caveats aside, it's exciting to watch how quickly the field is evolving. Not long ago, the idea of converting one cell type into another was nothing but a dream. Now, scientists (many of them CIRM grantees) are finding ever more ingenious ways of converting skin, fat and other starting tissues into embryonic-like stem cells, adult cell types, and now in-between progenitors, each of which could be useful in their own way for understanding and treating disease.

PNAS, April 26, 2011
CIRM Funding: Sheng Ding (RN1-00536-1); Stuart Lipton (RC1-00125-1); Maria Talantova (T2-00004)

- A.A.

The confusing (and ongoing) story of iPS vs. embryonic stem cells

It appears we weren't the only people to notice last week's convergence of reprogrammed iPS cell news -- first they are made better, then they are suggested to be worthless. USA Today ran a story summing up several years' worth of such news. (For those not up-to-speed on iPS cells, you can watch this video with UCLA's Jerome Zack talking about how the cells are made.)

The story goes something like this: One day, iPS cells reprogrammed from adult tissue are going to eliminate the need for embryonic stem cells. No destroying embryos!

Soon after, someone points out that the creation of iPS cells -- though cool -- requires inserting cancer-causing genes. Not good! They cause cancer! But then someone finds a better way, with no cancer genes. Good! But then iPS cells are shown to differ dramatically from embryonic stem cells. And they don't seem quite as willing to form all tissues. Confusing!

According to the USA Today story:

"Basically, we are looking at a lot of confusion," says Harvard stem cell scientist Alexander Meissner. "That's not to say one group is wrong and another is right. We have been making a lot of progress, but everyone is looking at the same problems from different sides."

The story mentioned last week's paper by Salk researchers showing a molecular memory in iPS cells and went on:

Combined with a September Nature paper showing similar memory signatures in mouse IPS cells and Scripps Research Institute researchers last month reporting more cancer genes in IPS cells compared to embryonic ones, things looked bad . "The finding suggests that (induced) cells may not be suitable substitutes for (embryonic) cells in modeling or treating disease," noted Nature science reporter Elie Dolgin.

Although iPS cells are clearly the source of some confusion in terms of their similarity to embryonic stem cells, they are still a great tool for mimicking disease. CIRM researchers at Salk have taken skin cells from people with ALS, matured those cells in a lab dish into the cells involved in the disease and learned details about the biology of that disease that would never have been possible without reprogrammed cells. (Here's a video about that work.)

Other grantees at the Parkinson's Research Institute are taking skin from people with Parkinson's disease, maturing those into the neurons involved in that disease, and using those cells that are genetically included to form Parkinson's disease to understand the disease and test drugs. (This video includes scientists at the Parkinson's Institute talking about that work.)

At Gladstone, CIRM grantees are generating heart tissue from the skin of people with genetic heart diseases and using those cells to screen drugs. (You can watch a video of Bruce Conklin talking about that work.)

In each case, it doesn't matter that iPS cells are not identical to embryonic stem cells. It matters that they are currently the only way to study mature disease-prone cells in a lab dish. Because those people with Parkinson's disease aren't giving up brain tissue and the heart disease patients aren't loaning out little chunks of their heart. But skin they can part with.

USA Today ends their story by instructing readers to hang on for a bumpy ride ahead as scientists resolve the meaning of the differences between iPS and embryonic stem cells. One day we'll know which cell type provides the best tool for treating and studying different diseases. In the mean time, USA Today is likely right that the ride won't be dull. 

- A.A.