Stem cell stories that caught our eye: update on Capricor’s heart attack trial; lithium on the brain; and how stem cells do math

Capricor ALLSTARToday our partners Capricor Therapeutics announced that its stem cell therapy for patients who have experienced a large heart attack is unlikely to meet one of its key goals, namely reducing the scar size in the heart 12 months after treatment.

The news came after analyzing results from patients at the halfway point of the trial, six months after their treatment in the Phase 2 ALLSTAR clinical trial which CIRM was funding. They found that there was no significant difference in the reduction in scarring on the heart for patients treated with donor heart-derived stem cells, compared to patients given a placebo.

Obviously this is disappointing news for everyone involved, but we know that not all clinical trials are going to be successful. CIRM supported this research because it clearly addressed an unmet medical need and because an earlier Phase 1 study had showed promise in helping prevent decline in heart function after a heart attack.

Yet even with this failure to repeat that promise in this trial,  we learned valuable lessons.

In a news release, Dr. Tim Henry, Director of the Division of Interventional Technologies in the Heart Institute at Cedars-Sinai Medical Center and a Co-Principal Investigator on the trial said:

“We are encouraged to see reductions in left ventricular volume measures in the CAP-1002 treated patients, an important indicator of reverse remodeling of the heart. These findings support the biological activity of CAP-1002.”

Capricor still has a clinical trial using CAP-1002 to treat boys and young men developing heart failure due to Duchenne Muscular Dystrophy (DMD).

Lithium gives up its mood stabilizing secrets

As far back as the late 1800s, doctors have recognized that lithium can help people with mood disorders. For decades, this inexpensive drug has been an effective first line of treatment for bipolar disorder, a condition that causes extreme mood swings. And yet, scientists have never had a good handle on how it works. That is, until this week.

evan snyder

Evan Snyder

Reporting in the Proceedings of the National Academy of Sciences (PNAS), a research team at Sanford Burnham Prebys Medical Discovery Institute have identified the molecular basis of the lithium’s benefit to bipolar patients.  Team lead Dr. Evan Snyder explained in a press release why his group’s discovery is so important for patients:

“Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks.”

The study, funded in part by CIRM, attempted to understand lithium’s beneficial effects by comparing cells from patient who respond to those who don’t (only about a third of patients are responders). Induced pluripotent stem cells (iPSCs) were generated from both groups of patients and then the cells were specialized into nerve cells that play a role in bipolar disorder. The team took an unbiased approach by looking for differences in proteins between the two sets of cells.

The team zeroed in on a protein called CRMP2 that was much less functional in the cells from the lithium-responsive patients. When lithium was added to these cells the disruption in CRMP2’s activity was fixed. Now that the team has identified the molecular location of lithium’s effects, they can now search for new drugs that do the same thing more effectively and with fewer side effects.

The stem cell: a biological calculator?


Can stem cells do math?

Stem cells are pretty amazing critters but can they do math? The answer appears to be yes according to a fascinating study published this week in PNAS Proceedings of the National Academy of Sciences.

Stem cells, like all cells, process information from the outside through different receptors that stick out from the cells’ outer membranes like a satellite TV dish. Protein growth factors bind those receptors which trigger a domino effect of protein activity inside the cell, called cell signaling, that transfers the initial receptor signal from one protein to another. Ultimately that cascade leads to the accumulation of specific proteins in the nucleus where they either turn on or off specific genes.

Intuition would tell you that the amount of gene activity in response to the cell signaling should correspond to the amount of protein that gets into the nucleus. And that’s been the prevailing view of scientists. But the current study by a Caltech research team debunks this idea. Using real-time video microscopy filming, the team captured cell signaling in individual cells; in this case they used an immature muscle cell called a myoblast.


Behavior of cells over time after they have received a Tgf-beta signal. The brightness of the nuclei (circled in red) indicates how much Smad protein is present. This brightness varies from cell to cell, but the ratio of brightness after the signal to before the signal is about the same. Image: Goentoro lab, CalTech.

To their surprise the same amount of growth factor given to different myoblasts cells led to the accumulation of very different amounts of a protein called Smad3 in the cells’ nuclei, as much as a 40-fold difference across the cells. But after some number crunching, they discovered that dividing the amount of Smad3 after growth factor stimulation by the Smad3 amount before growth stimulation was similar in all the cells.

As team lead Dr. Lea Goentoro mentions in a press release, this result has some very important implications for studying human disease:

“Prior to this work, researchers trying to characterize the properties of a tumor might take a slice from it and measure the total amount of Smad in cells. Our results show that to understand these cells one must instead measure the change in Smad over time.”

Bipolar Disorder-in-a-Dish: Game On for Finding New Drugs

Amy Winehouse: a tremendous talent lost to bipolar disorder. Credit: Wikimedia Commons

Amy Winehouse: a tremendous talent lost to bipolar disorder. Credit: Wikimedia Commons

The tragic path of biopolar disorder
Ernest Hemingway, Kurt Cobain, Amy Winehouse and Virginia Woolf – the world lost their creativity too soon. Each took their own life or succumbed to substance abuse, most likely due to their struggles with bipolar disorder. Also called manic depression, bipolar disorder is one of the most severe types of mental illness. It’s characterized by episodes of extreme manic behavior preceded or followed by bouts of devastating depression. Bipolar disorder is thought to affect 3-5% of the world’s population and, if left untreated, has a 15% risk of death by suicide.

Lithium is the most effective treatment for long term management of the disorder though the drug’s mechanism of action isn’t well understood. Sadly, many people who are bipolar don’t respond to lithium and instead must wade through a complex mix of drugs that attempts to tackle the varied symptoms.

Imaging studies suggest unique changes in the bipolar brain and studies of twins show a genetic component but scientists are far from unraveling the direct causes of bipolar disorder. Now, exciting research at the Salk Institute reported in Nature provides a powerful new tool for not only understanding the disease at a cellular level but also finding new drug treatments.

“The cells of these patients really are different”
Using induced pluripotent stem cell (iPSC) technology, the Salk team successfully grew nerve cells, or neurons, in the lab from skin samples of six people with bipolar disorder as well as from healthy individuals. When compared to the healthy neurons, the researchers saw a higher sensitivity of the bipolar neuron to stimuli. Jerome Mertens, a postdoctoral fellow and the lead author of the study, explained the result further in a Salk Institute press release:

“Neurons are normally activated by a stimuli and respond. The cells we have from all six patients are much more sensitive in that you don’t need to activate them very strongly to see a response.”

And Salk professor Rusty Gage, a CIRM grantee and the senior scientist of the study, points out that these cells represent a game-changer for the study of bipolar disorder:

“Researchers hadn’t all agreed that there was a cellular cause to bipolar disorder. So our study is important validation that the cells of these patients really are different.”

Lithium response in lab dish = lithium response in patients
And now comes the really exciting part. The team next studied the effects of lithium on these six bipolar patients’ cells. Three of the patients were responders to lithium treatment while the other three were not helped by the drug. When grown in lithium, the cells from the lithium responders became less sensitive, you might even say less “manic”, to stimuli while the cells from the lithium non-responders remained hyperactive.


Salk scientists discover cellular differences between brain cells from bipolar patients that respond to lithium and those that don’t. Neurons (white/red) from a subset of bipolar patients show changes in their electrical activity in response to lithium.Credit: Salk Institute

So the response of these “disease in a dish” cells to lithium corresponds perfectly with the lithium response in the patients. This result will undoubtedly propel the use of these iPSC-derived neurons to examine the causes of the diseases at a cellular and molecular level. Not only that but the cells should become a key resource for testing lithium alternatives that may help the portion of the bipolar population that doesn’t response to lithium.

In order words, this use of iPSC technology begins a new chapter in the effort to free sufferers from the life-long grip of bipolar disorder.

CIRM’s got skin in the game too
The incredible power of iPSCs to examine human disease like never before is not lost on the CIRM team. That’s why we’re so excited that our iPSC bank is now open for business. It’s a major effort by the agency to create a public stem cell bank developed from thousands of individuals. These cells will be available to scientists worldwide to better understand and to develop therapies for diseases of heart, lung and liver as well as neurodegenerative and childhood neurological disorders.

Related Links:
Seminar video: Carol Marchetto, Salk Institute staff scientist, discusses the study in greater detail