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.”

Unlocking the secrets of how stem cells decide what kind of cell they’re going to be

Laszlo Nagy, Ph.D., M.D.

Laszlo Nagy, Ph.D., M.D.: Sanford Burnham Prebys Medical Discovery Institute

Before joining CIRM I thought OCT4 was a date on the calendar. But a new study says it may be a lot closer to a date with destiny, because this study says OCT4 helps determine what kinds of cell a stem cell will become.

Now, before we go any further I should explain for people who have as strong a science background as I do – namely none – that OCT4 is a transcription factor, this is a protein that helps regulate gene activity by turning certain genes on at certain points, and off at others.

The new study, by researches at Sanford Burnham Prebys Medical Discovery Institute (SBP), found that OCT4 plays a critical role in priming genes that cause stem cells to differentiate or change into other kinds of cells.

Why is this important? Well, as we search for new ways of treating a wide variety of different diseases we need to find the most efficient and effective way of turning stem cells into the kind of cells we need to regenerate or replace damaged tissue. By understanding the mechanisms that determine how a stem cell differentiates, we can better understand what we need to do in the lab to generate the specific kinds of cells needed to replace those damaged by, say, heart disease or cancer.

The study, published in the journal Molecular Cell, shows how OCT4 works with other transcription factors, sometimes directing a cell to go in one direction, sometimes in another. For example, it collaborates with a vitamin A (aka retinoic acid) receptor (RAR) to convert a stem cell into a neuronal precursor, a kind of early stage brain cell. However, if OCT4 interacts with another transcription factor called beta-catenin then the stem cell goes in another regulatory direction altogether.

In an interview with PhysOrg News, senior author Laszlo Nagy said this finding could help develop more effective methods for producing specific cell types to be used in therapies:

“Our findings suggest a general principle for how the same differentiation signal induces distinct transitions in various types of cells. Whereas in stem cells, OCT4 recruits the RAR to neuronal genes, in bone marrow cells, another transcription factor would recruit RAR to genes for the granulocyte program. Which factors determine the effects of differentiation signals in bone marrow cells – and other cell types – remains to be determined.”

In a way it’s like programming all the different devices that are attached to your TV at home. If you hit a certain combination of buttons you get to one set of stations, hit another combination and you get to Netflix. Same basic set up, but completely different destinations.

“In a sense, we’ve found the code for stem cells that links the input—signals like vitamin A and Wnt—to the output—cell type. Now we plan to explore whether other transcription factors behave similarly to OCT4—that is, to find the code in more mature cell types.”



CIRM scholar Ke Wei talks heart regeneration

Ke Wei

Ke Wei

“How do you mend a broken heart?” was the topic of one of our recent Stem Cellar blogs highlighting a stellar CIRM-funded publication on the regenerative abilities of the protein FSTL1 following heart injury. One of the master-minds behind this study is co-first author Ke Wei. Ke is a postdoc in Dr. Mark Mercola’s lab at the Sanford Burnham Prebys Medical Discovery Institute located in balmy southern California. He also happens to be one of our prized CIRM scholars.


Cross sections of a healthy (control) or injured mouse heart. Injured hearts treated with patches containing FSTL1 show the most recovery of healthy heart tissue (red). Image adapted from Wei et al. 2015)

Upon hearing of Ke’s important and exciting accomplishments in the field of regenerative medicine for heart disease, we called him up to learn more about his scientific accomplishments and aspirations.

Q: Tell us about your research background and how you got into this field?

KW: I went to UCLA for my graduate school PhD, and I studied under Dr. Fabian Chen focusing on heart development. At that time, I mainly worked on very early heart development and other tissues like smooth muscle cells. For my graduate thesis work, I found that particular genes were important for smooth muscle development.

So I was trained as a heart developmental biologist, but after my PhD, I came to the Burnham Institute and I joined two labs: Dr. Mark Mercola and Dr. Pilar Ruiz-Lozano. They co-mentored me for the first couple of years of my postdoc. Mark is interested in using stem cells and high throughput screens to identify pharmaceutical compounds for inducing heart regeneration and treating heart diseases. Pilar is interested in the epicardium, the outer layer of the heart, which is known to play important roles during heart development. When I joined their labs, they had combined forces to study how the epicardium affects heart development and heart diseases.

In their labs, I used my developmental biologist background to combine in vitro stem cells based screening studies (Mark) and in vivo mouse embryonic heart development studies (Pilar) to dissect the function of the epicardium on heart development and disease.

Q: Tell us about your experience as a CIRM scholar and what you were able to accomplish.

KW: My two years of CIRM fellowship were separated but my focus was the same for both CIRM-funded periods: to understand the effect of the epicardium on heart development and diseases.

In my first project in 2008, we tried to generate an in vitro model of mouse epicardial cells and used those cells to study their influence on cardiac differentiation using both in vitro and in vivo experiments. We ran into a lot of technical difficulties, so at that time, we decided to switch to using existing in vitro epicardial cell lines, and using those to study their influence on cardiomyocytes (heart muscle cells).

In my second year of CIRM funding in 2011, we identified the genes and proteins that can promote immature cardiomyocytes to proliferate, and put them in vivo and it worked. So the success of our publication all started from my second year of CIRM-fellowship.

Q: What benefits did you experience as a CIRM scholar?

KW: I’ve really enjoyed being a CIRM scholar and took advantage of the resources they provided me over the years. One of the benefits I enjoyed the most was attending the CIRM annual meetings and retreats. I was able to talk with a lot of scientists with different backgrounds, and that really expanded my horizons.

As you can see from our paper in Nature, it’s definitely not only a developmental biologist paper. It’s actually very clinical and collaborative, and it was done by many different groups working together. By going to CIRM conferences and meeting all the other CIRM fellows, I got a lot of new ideas, and those ideas encouraged me to collaborate with more scientists. These events really encouraged me to look beyond the thoughts of a developmental biologist.

Our paper is co-authored by me and Vahid Serpooshan from Stanford. We co-first authored this paper, and my work mainly involved the in vitro studies that identified the regenerative proteins and their function in heart injury. Vahid’s approach was more bioengineering focused. He produced the FSTL1 patch, put it in the rodent heart, and conducted all the other in vivo studies. It was a perfect collaboration to push this project for publication in a high level journal like Nature.

Q: What is the big picture of your research and your future goals?

KW: I plan to stay in academia. The key thing about heart diseases is that heart regeneration is very limited. Using our approach, we found one particular protein that’s important to the regenerative process, and in reality, its concentration is very low in the heart when it’s infarcted (injured). I think we have set up a pretty good system to test all possible therapeutic means in the lab, including proteins from the epicardium, small molecules, microRNAs and other compounds to activate cardiomyocyte proliferation. I plan to focus on understanding the mechanisms for why cardiomyocytes stop proliferating in the adult heart, and what new approaches we can pursue to promote their expansion and regenerative abilities. The FSTL1 story is the start of this, and I will try to find new factors that can promote heart regeneration.

Q: Will your work involve human stem cell models?

KW: To make this study clinically relevant, we included the swine models. We are definitely testing FSTL1 in human cells right now. Currently we can produce a huge amount of the human cardiomyocytes. They seem to be at a different stage than rodent cells so we are optimizing the system to perform screens for human cell proliferation. When that system is set up, then anything that comes out of the screen will be much more relevant to clinical studies in humans.

Q: What is your favorite thing about being a scientist?

Knowing that the information I acquire through experiments is new to mankind, and that my actions expand the horizon of combined human knowledge, even just for a tiny bit, is a huge satisfaction to me as a scientist.