Stem cell stories that caught our eye: lab-grown kidneys that work, finding blood stem cells’ home and colitis

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Lab grown kidneys able to take a leak. While a few teams have been able to grow parts of kidneys in the lab using stem cells, they could never show full function because kidneys are not a closed system. They need connecting plumbing and a shutterstock_251360653bladder to collect fluid before urine can be expelled. Now, a team in Japan has built kidneys as well as those other parts in the lab. When they were implanted in rats and pigs and connected to the animals’ own plumbing the man-made organs successfully peed.

The BBC ran a story on the work that included a quote from noted stem cell expert Chris Mason of University College, London:

”This is an interesting step forward. The science looks strong and they have good data in animals. But that’s not to say this will work in humans. We are still years off that. It’s very much mechanistic. It moves us closer to understanding how the plumbing might work.”

The team published the research in the U.S. Proceedings of the National Academy of Sciences.

Seeing through bone to track stem cells. Yes we know blood-forming stem cells reside in bone marrow, but that is a pretty big base of operations. We really haven’t known where in the marrow they tend to hang out and in what sort of groupings. A team at Children’s Research Institute at the University of Texas Southwestern published research this week using new imaging techniques to map the home of all the blood stem cells in marrow and it showed some surprising results.

“The bone marrow and blood-forming stem cells are like a haystack with needles inside. Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located,” said UT’s Sean Morrison in a press release posted by Technology Networks.

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles – all the blood-forming stem cells that are present in the bone marrow – and to know exactly where they are and how far they are from every other cell type.”

They found the blood-forming stem cells clustered in the center of the bone marrow rather than near the edges of the bone as was presumed. This improved understanding of the stem cells’ natural environment should make it easier to replicate the cells behavior in the lab and, in turn, lead to improved stem cell therapies.

Help for colitis patients resistant to therapy. About two-thirds of patients with colitis and Crohn’s disease do not respond to one of the leading medications that blocks a protein considered key to the inflammatory process, Tumor Necrosis Factor (TNF). A CIRM-funded team at the Children’s Hospital Los Angeles published research this week suggesting why and offering possible new options for treatment.

“Understanding this mechanism allows us to target new therapeutic approaches for patients who don’t respond to current therapies,” said principal investigator Brent Polk in a university press release posted at Eurekalert.

The mechanism surprised his team. They found that TNF in these patients actually protected against inflammation by inhibiting one type of the immune system’s T cells. The interplay between TNF and those culprit T cells now becomes a target to therapeutic intervention.

Funding a clinical trial for deadly cancer is a no brainer

The beast of cancers
For a disease that is supposedly quite rare, glioblastoma seems to be awfully common. I have lost two friends to the deadly brain cancer in the last few years. Talking to colleagues and friends here at CIRM, it’s hard to find anyone who doesn’t know someone who has died of it.


Imagery of glioblastoma, a deadly brain cancer,  from ImmunoCellular’s website

So when we got an application to fund a Phase 3 clinical trial to target the cancer stem cells that help fuel glioblastoma, it was really a no brainer to say yes. Of course it helped that the scientific reviewers – our Grants Working Group or GWG – who looked at the application voted unanimously to approve it. For them, it was great science for an important cause.

Today our Board agreed with the GWG and voted to award $19.9 million to LA-based ImmunoCellular Therapeutics to carry out a clinical trial that targets glioblastoma cancer stem cells. They’re hoping to begin the trial very soon, recruiting around 400 newly diagnosed patients at some 120 clinical sites around the US, Canada and Europe.

There’s a real urgency to this work. More than 50 percent of those diagnosed with glioblastoma die within 15 months, and more than 90 percent within three years. There are no cures and no effective long-term treatments.

As our President and CEO, Dr. Randy Mills, said in a news release:

 “This kind of deadly disease is precisely why we created CIRM 2.0, our new approval process to accelerate the development of therapies for patients with unmet medical needs. People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months. We wanted a process that was more responsive to the needs of patients, and that could help companies like ImmunoCellular get their potentially life-saving therapies into clinical trials as quickly as possible.”

The science
The proposed treatment involves some rather cool science. Glioblastoma stem cells can evade standard treatments like chemotherapy and cause the recurrence and growth of the tumors. The ImmunoCellular therapy addresses this issue and targets six cell surface proteins that are found on glioblastoma cancer stem cells.

The researchers take immune cells from the patient’s own immune system and expose them to fragments of these cancer stem cell surface proteins in the lab. By re-engineering the immune cells in this way they are then able to recognize the cancer stem cells.

My colleague Todd Dubnicoff likened it to letting a bloodhound sniff a piece of clothing from a burglar so it’s able to recognize the scent and hunt the burglar down.  When the newly trained immune system cells are returned to the patient’s body, they can now help “sniff out” and hopefully kill the cancer stem cells responsible for the tumor’s recurrence and growth.

Like a bloodhound picking up the scent of a burglar, ImmunoCellular's therapy helps the immune system track down brain cancer stem cells (source: wikimedia commons)

Like a bloodhound picking up the scent of a burglar, ImmunoCellular’s therapy helps the immune system track down brain cancer stem cells (source: Wikimedia Commons)

Results from both ImmunoCellular’s Phase 1 and 2 trials using this approach were encouraging, showing that patients given the therapy lived longer than those who got standard treatment and experienced only minimal side effects.

Turning the corner against glioblastoma
There’s a moment immediately after the Board votes “yes” to fund a project like this. It’s almost like a buzz, where you feel that you have just witnessed something momentous, a moment where you may have turned the corner against a deadly disease.

We have a saying at the stem cell agency: “Come to work every day as if lives depend on it, because lives depend on it.” On days like this, you feel that we’ve done something that could ultimately help save some of those lives.

CIRM Scholar Spotlight: Matt Donne on Lung Stem Cells

CIRM has funded a number of educational and research training programs over the past ten years to give younger students and graduate/postdoc scholars the opportunity to explore stem cell science.

Two of the main programs we support are the Bridges and the CIRM Scholars Training Program. These programs fund future scientists from an undergraduate to postdoctoral level with a goal of creating “training programs that will significantly enhance the technical skills, knowledge, and experience of a diverse cohort of… trainees in the development of stem cell based therapies.”

The Stem Cellar team was interested to hear from Bridges and CIRM scholars themselves about their experience with these programs, how their careers have benefited from CIRM funding, and what research accomplishments they have under their belt. We were able to track some of these scholars down, and will be publishing a series of interview-style blogs featuring them over the next few months.

Matt Donne

Matt Donne

We start off with a Matt Donne, a PhD student at the University of California, San Francisco (UCSF) in the Developmental and Stem Cell Biology graduate program. Matt is a talented scientist and has a pretty cool story about his research training path. I sat down with Matt to ask him a few questions.

Q: Tell us how you got into a Stem Cell graduate program at UCSF.

MD: I was fortunate to have Dr. Carmen Domingo from San Francisco State support my application into the CIRM Bridges Program. I’d been working for Dr. Susan Fisher at UCSF for a couple of years and realized that I wanted to get a PhD and go to UCSF. I thought the best way to do that was improve my GPA and get a masters degree in stem cell biology. I applied to the CIRM program at SF State, and was accepted.

The Bridges Program has been a great feeder platform to get students more science experience exposure than they would have otherwise received, and prepares them well to move on to competitive graduate schools.

After receiving my Masters degree, I was admitted into the first year of the Developmental and Stem Cell Biology program at UCSF. When the opportunity to apply for a training grant from CIRM came about between my first and second year of at UCSF, I knew I had to give it a chance and apply. With the help of my mentor, Dr. Jason Rock, I wrote a solid proposal and was awarded the fellowship.

While at SF State, Carmen was extremely supportive and always available for her students. Since then, many of us still keep in touch and more have joined the UCSF graduate school community.

Q: Can you describe your graduate research?

MD: The field of regenerative medicine is searching for ways to allow us to repair injuries similar to how the Marvel Comic Wolverine can repair his wounds in the movies. One interesting fact which has been known for several decades, but has not been able to be investigated more deeply until now, is the innate ability for the adult lung to regrow lost lung tissue without any sort of intervention. My thesis focuses on defining the molecular mechanisms and stem cell niches that allow for this normal, healthy adult lung tissue growth. The working hypothesis is if we can understand what makes a cell undergo healthy tissue proliferation and differentiation, we could stimulate this response to cure individuals who suffer from diseases such as chronic obstructive pulmonary disease (COPD). Similarly, if we understand how a cell decides to respond in a diseased way, we could stop or revert the disease process from occurring.

One of the models we use in our lab is a “pneumosphere” culture. We essentially grow alveoli, which are the site of gas exchange in the lung, in a dish to attempt to understand how specific alveolar stem cells signal and interact with one another. This information will teach us how these cells behave so we can in turn either promote a healthy response to injury or, potentially, stop the progression of unhealthy cell responses. The technique of growing alveoli in a dish allows us to cut down on the “noise” and focus on major cellular pathways, which we can then more selectively apply to our mouse model systems.

Pneumospheres. (Photo by Matt Donne)

Pneumospheres or “lung cells in a dish”. (Photo by Matt Donne)

Lung cells.

Lung pneumospheres under a microscope. (Photo by Matt Donne)

We are now in the process of submitting a paper demonstrating some of the molecular players that are involved in this regenerative lung response. Hopefully the reviewers will think our paper is as awesome we as believe it to be.

Q: How has being a CIRM scholar benefited your graduate research career?

MD: Starting in my second year at UCSF, I was awarded the CIRM fellowship. I think it helped the lab to have the majority of my stipend covered through the CIRM fellowship, and personally I was very excited about the $5,000 discretionary budget. These monies allowed me to go to conferences every year for the past three years, and also have helped to support the costs of my experiments.

The first conference I attended was a Gordon Conference in Italy on Developmental Biology. There I was able to learn more about the field and also make friends with many professors, students, and postdocs from around the world. Last year, I went to my first lung-specific conference, and attended again this year. That has been one of the highlights of my PhD career. While there, one is able to speak and interact with professors whose names are seen in many textbooks and published papers. I never thought I would be able to so casually interact with them and develop relationships. Since then, I have been able to work on small collaborations with professors from across the US.

It was great that I could go to these conferences and establish important relationships with professors without being a major financial burden to my Professor. Plus, it has been hugely beneficial for my career as I now have professors whom I can reach out to as I look towards my future as a scientist.

Q: What other benefits did the CIRM scholars program provide you?

MD: Dr. Susan Fisher has been in charge of the CIRM program at UCSF. She organized lunch-time research talks that involved both academic as well as non-academic leaders in the field. I enjoyed the extra exposure to new fields of stem cell biology as well as the ability to learn more about the start-up and non-academic world. There are not many programs that offer this type of experience, and I felt fortunate to be a part of it. Also, the free lunches on occasion were a nice perk for a grad student living in San Francisco!

I attended the CIRM organized conferences whenever they happened. It’s always great presenting at or attending poster sessions at these events, seeing familiar faces and meeting new people. I took full advantage of the learning and networking that CIRM allowed me to do. The CIRM elevator pitch competition was really cool too. I didn’t win, came in third, but I enjoyed the challenge of trying to break down my thesis project into a digestible one-minute pitch.

Q: Where do you see the field of lung biology and regenerative medicine heading?

MD: My take away from the research conferences I have attended with the help of CIRM-funding is that we are in a very exciting time for lung stem cell research. The field overall is still young, but there are many labs across the world now working on a “lung mapping project” to better define stem cell populations in the lung. I see this research in the future translating in to regenerative therapies by which diseased cells/tissue will be targeted to actually stop the disease progression, and in turn possibly repair and regenerate healthy new tissue. This research has wide reaching implications as it has the potential to help everyone from a premature baby more quickly develop mature healthy lungs, to adults suffering from COPD brought on by environmental factors, such as air pollution. As many scientists are often quoted, “This is a very exciting time for our field.”

Q: What are your future plans?

MD: I expect to graduate in about a year’s time. In the future, I want to pursue a career focusing on the social impact of science. I aspire to be someone like UCSF’s former chancellor Dr. Susan Desmond-Hellmand. It’s really cool to go from someone who was the president of product development at Genentech, to chancellor at UCSF, to now president of the Bill and Melinda Gates Foundation. Bringing science to impact society in that way is what I hope to do with my future.

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How Brain Stem Cells Could Stay Forever Young

As we age, so do the cells that make up our bodies. To keep us spry as we get older, our bodies rely on adult stem cells to replace the cells in our tissues and organs. Adult stem cells can only generate cell types specific to the organ or tissue that they live in. For instance, heart stem cells can only help regenerate or repair the heart, same for brain stem cells and the brain, etc.

While adult stem cells have built-in mechanisms to help them avoid the aging process for as long as possible, they can only delay the inevitable for so long. So as the function of our bodies decline, so does adult stem cell function and with it our ability to regenerate damaged tissue.

But now a new study has found out what happens to cause the aging of adult stem cells and points at ways to avoid it and keep these stem cells “forever young.”

Brain stem cells stay youthful

A group from Zurich, Switzerland studied how brain stem cells stay young as the brain ages. In a study published in Science on Friday, they found that young brain stem cells divide in a way that routes damaged proteins and aging-related factors away from the daughter stem cells and into their non-stem cell progeny, thus keeping brain stem cells healthy and youthful.


Brain stem cells divide asymmetrically into a daughter stem cell and a non-stem daughter cell that can differentiate into other brain cells (Image adapted from Berika et al., 2014).

The Zurich group took a closer look at brain stem cells in adult mouse brains and found that they divide asymmetrically. This means that instead of equally dividing its cellular components between two daughter cells, the mother cell instead herds all of the damaged proteins and aging factors into the non-stem daughter cell, leaving the new stem cell unexposed to cell damage. In this way, the new stem cell is protected and is able to maintain its regenerative capacity.

A barrier against aging?

Brain stem cells are able to preferentially shuttle damaged proteins into their non-stem cell progeny by a diffusion barrier called the endoplasmic reticulum (ER). The ER is a membrane structure in cells that has a number of important functions including deciding what factors or proteins end up in which cells.

The authors observed that during the division of brain stem cells, the ER forms a barrier between the non-stem and stem cell progeny that keeps the damaged proteins and aging factors in the non-stem daughter cell. This ER barrier remains intact during the division of young brain stem cells, however, they weren’t sure this was the case with older brain stem cells.

The scientists watched older brain stem cells to see if this anti-aging barrier was able to hold up with advancing age. They observed that this barrier actually weakens with age and allows aging factors to go with the stem cell progeny. This happens because an important cell structure called the nuclear lamina, which regulates cell division, doesn’t function properly in the old stem cells. When they disrupted the lamina structure in young brain stem cells, as expected, the anti-aging barrier couldn’t properly block the transfer of aging-factors into the new daughter stem cells.


Young brain stem cells on the left divide asymmetrically and have a barrier that keeps age-related damage in the non-stem daughter cell (red). This barrier weakens in older brain stem cells and aging factors are transferred to the stem cell progeny. (Moore et al., 2015)


Thus it seems that brain stem cells maintain their youth by generating diffusible barriers that block the transfer of damaged proteins and aging factors into their stem cell progeny during cell division. The strength of this barrier weakens with age, and when this happens, aging factors are more evenly divided between the non-stem and stem cell progeny, potentially causing stem cell damage and reducing their regenerative function.

Anti-aging implications

The authors note at the end of their report that further studies should be done to determine whether this anti-aging mechanism is unique to brain stem cells or if it occurs in other adult stem cells or cancer cells which display stem cell like properties. If similar anti-aging barriers exist, then targeting the age-related breakdown of this barrier could be a potential strategy to keep adult stem cells forever young and humans feeling and acting younger for a little longer.

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Helping patient’s fight back against deadliest form of skin cancer

Caladrius Biosciences has been funded by CIRM to conduct a Phase 3 clinical trial to treat the most severe form of skin cancer: metastatic melanoma. Metastatic melanoma is a disease with no effective treatment, only around 15 percent of people with it survive five years, and every year it claims an estimated 10,000 lives in the U.S.

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The Caladrius team has developed an innovative cancer treatment that is designed to target the cells responsible for tumor growth and spread. These are called cancer stem cells or tumor-initiating cells. Cancer stem cells can spread in the body because they have the ability to evade the body’s immune defense and survive standard anti-cancer treatments such as chemotherapy. The aim of the Caladrius treatment is to train the body’s immune system to recognize the cancer stem cells and attack them.

Attacking the cancer

The treatment process involves taking a sample of a patient’s own tumor and, in a laboratory, isolating specific cells responsible for tumor growth . Cells from the patient’s blood, called “peripheral blood monocytes,” are also collected. The mononucleocytes are responsible for helping the body’s immune system fight disease. The tumor and blood cells (after maturation into dendritic cells) are then combined and incubated so that the patient’s immune cells become trained to recognize the cancer cells.

After the incubation period, the patient’s immune cells are injected back into their body where they generate an immune response to the cancer cells. The treatment is like a vaccine because it trains the body’s immune system to recognize and rapidly attack the source of disease.

Recruiting the patients

Caladrius has already dosed the first patient in the trial (which is double blinded so no one knows if the patient got the therapy or a placebo) and hopes to recruit 250 patients altogether.

This is the first Phase 3 trial that CIRM has funded so we’re obviously excited about its potential to help people battling this deadly disease.  In a recent news release David J. Mazzo, the CEO of Caladrius echoed this excitement, with a sense of cautious optimism:

“The dosing of the first patient in this Phase 3 trial is an important milestone for our Company and the timing underscores our focus on this program and our commitment to impeccable trial execution. We are delighted by the enthusiasm and productivity of the team at Jefferson University (where the patient was dosed) and other trial sites around the country and look forward to translating that into optimized patient enrollment and a rapid completion of the Phase 3 trial.”

And that’s the key now. They have the science. They have the funding. Now they need the patients. That’s why we are all working together to help Caladrius recruit patients as quickly as possible. Because their work perfectly reflects our mission of accelerating the development of stem cell therapies for patients with unmet medical needs.

You can learn more about what the study involves and who is eligible by clicking here.

Stem cell stories that caught our eye: new CRISPR fix for sickle cell disease, saving saliva stem cells, jumping genes in iPSCs and lung stem cells.

An end run around sickle cell disease with CRISPR
The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)

Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.

So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.

But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:

“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”

Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.

Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth?
I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.

Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.

Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.

Keeping a Lid on Jumping Genes
Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.

While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.

To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.

Retrotransposons: curious pieces of DNA that can be transcribed into RNA, copied into DNA, and inserted to a new spot in your chromosomes.

The duplication and insertion of transposons into our chromosomes can be bad news for a cell

Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.

So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.

The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.

Great hope for lung stem cells
Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.

In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.

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The Ogawa-Yamanaka Prize Crowns Its First Stem Cell Champion

A world of dark

Imagine if you woke up one day and couldn’t see. Your life would change drastically, and you would have to painfully relearn how to function in a world that heavily relies on sight.

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

While most people don’t lose their sight overnight, many suffer from visual impairments that slowly happen over time. Glaucoma, cataracts, and macular degeneration are examples of debilitating eye diseases that eventually lead to blindness.

With almost 300 million people world wide with some form of visual impairment, there’s urgency in the scientific community to develop safe therapies for clinical applications. One of the most promising strategies is using human induced pluripotent stem (iPS) cells derived from patients to generate cell types suitable for transplantation into the human eye.

However, this task is more easily said than done. Safety, regulatory, and economical concerns make the process of translating iPS cell therapies from the bench into the clinic an enormous challenge worthy only of a true scientific champion.

A world of light

Dr. Masayo Takahashi

Dr. Masayo Takahashi

Meet Dr. Masayo Takahashi. She is a faculty member at the RIKEN Centre for Developmental Biology, a prominent female scientist in Japan, and a bona fide stem cell champion. Her mission is to cure diseases of blindness using iPS cell technology.

Since the Nobel Prize-winning discovery of iPS cells by Dr. Shinya Yamanaka eight years ago, Dr. Takahashi has made fast work using this technology to generate specific cells from human iPS cells that can be transplanted into patients to treat an eye disease called macular degeneration. This disease results in the degeneration of the retina, an area in the back of the eye that receives light and translates the information to your brain to produce sight.

Dr. Takahashi generates cells called retinal pigment epithelial (RPE) cells from human iPS cells that can replace lost or dying retinal cells when transplanted into patients with macular degeneration. What makes this therapy so exciting is that Dr. Takahashi’s iPS-derived RPE cells appear to be relatively safe and don’t cause an immune system reaction or cause tumors when transplanted into humans.

Because of the safety of her technology, and the unfulfilled needs of millions of patients with eye diseases, Dr. Takahashi made it her goal to take iPS cells into humans within five years of Dr. Yamanaka’s discovery.

Ogawa-Yamanaka Stem Cell Prize

It’s no surprise that Dr. Takahashi succeeded in her ambitious goal. Her cutting edge work has led to the first clinical trial using iPS cells in humans, specifically treating patients with macular degeneration. In September 2014, the first patient, a 70-year-old Japanese woman, received a transplant of her own iPS-derived RPE cells and no complications were reported.

Currently, the trial is on hold “as part of a safety validation step and in consideration of anticipated regulatory changes to iPS cell research in Japan” according to a Gladstone Institute news release. Nevertheless, this first iPS cell trial in humans has overcome significant regulatory hurdles, has set an important precedent for establishing the safety of stem cell therapies, and has given scientists hope that iPS cell therapies can become a reality.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

For her accomplishments, Dr. Takahashi was recently awarded the first ever Ogawa-Yamanaka Stem Cell Prize and honored at a special event held at the Gladstone Institutes in San Francisco yesterday. This prize was established by a generous gift from Mr. Hiro Ogawa in collaboration with Dr. Shinya Yamanaka and Dr. Deepak Srivastava at the Gladstone Institutes. The award recognizes scientists who conduct translational iPS cell research that will eventually be applied to patients in the clinic.

In an interview with CIRM, Dr. Deepak Srivastava, the Director of the Gladstone Institute of Cardiovascular Disease and the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, described the prestigious prize and the ceremony held at the Gladstone to honor Dr. Takahashi:

Dr. Deepak Srivastava

The Ogawa-Yamanaka prize prize is meant to incentivize and honor those whose work is advancing the translational use of stem cells for regenerative medicine. Dr. Masayo Takahashi is a pioneer in pushing the technology of iPS cell-derived cell types and actually introducing them into people. She’s the very first person in the world to successfully overcome all the regulatory barriers and the scientific barriers to introduce this new type of stem cell into a patient. And she’s done so for a condition of blindness called macular degeneration, which affects millions of people world wide, and for which there are very few treatments currently. We are honoring her with this prize for her pioneering efforts at making this technology one that can be applied to patients.

The new world that iPS cells will bring

As part of the ceremony, Dr. Takahashi gave a scientific talk on the new world that iPS cells will bring for patients with diseases that lack cures, including those with visual impairments. The Stem Cellar team was lucky enough to interview Dr. Takahashi as well as attend her lecture during the Gladstone ceremony. We will cover both her talk and her interview with CIRM in an upcoming blog.

The Stem Cellar team at CIRM was excited to attend this momentous occasion, and to know that CIRM-funding has supported many researchers in the field of iPS cell therapy and regenerative medicine. We would like to congratulate Dr. Takahashi on her impressive and impactful accomplishments in this area and look forward to seeing progress in iPS cell trial for macular degeneration.


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Patching up a Broken Heart with FSTL1

Get-Over-Heartbreak-Step-08How do you mend a broken heart? It’s a subject that songwriters have pondered for generations, without success. But if you pose the same question to a heart doctor, they would give you a number of practical options that focus on the prevention or management of the physical symptoms you are dealing with.

That’s because heart disease is complicated. There are many different types of diseases that affect the health and function of the heart. And once damage happens to your heart, say from a heart attack, it’s really hard to fix.

New regenerative factor for heart disease

Scientists from Stanford University, the University of California, San Diego, and the Sanford-Burnham-Prebys Medical Discovery Institute have teamed up to figure out how to fix a broken heart. In a CIRM-funded study published today in the journal Nature, the group reported that the gene follistatin-like 1 (FSTl1) has the ability to regenerate heart tissue when it’s delivered within a patch to the injured heart.


The different layers of the heart.

The wall of the heart is made up of three different layers: the endocardium (inner), myocardium (middle), and epicardium (outer). The epicardium not only protects the inner two layers of the heart, but also supports the growth of the fetal heart.

The group decided to study epicardial cells to determine whether these cells produced specific factors that protect or even regenerate adult heart tissue. They took epicardial cells from rodents and cultured them with heart cells (called cardiomyocytes), and found that the heart cells divided and reproduced much more quickly when cultured with the epicardial cells. This suggested that the epicardial cells might secrete factors that promote the expansion of the heart cells.

Patching up a broken heart

They next asked whether factors secreted from epicardial cells could improve heart function in mice after heart injury. They designed and engineered tiny patches that contained a cocktail of special epicardial factors and sewed them onto the heart tissue of mice that had just experienced the equivalent of a human heart attack. When they monitored these mice two weeks later, they saw an improvement in heart function in mice with the patch compared to mice without.

When they analyzed the cocktail of epicardial factors in the patch, they identified one factor that had potential for regenerating heart tissue. It was FSTL1. To test its regenerative abilities, they cultured rodent heart cells in a dish and treated them with FSTL1 protein. This treatment caused the heart cells to divide like crazy, thus proving that FSTL1 had regenerative qualities.

Moving from the dish into animal models, the scientists explored which layers of the heart FSTL1 was expressed in after heart injury. In healthy hearts, FSTL1 is expressed in the epicardium. However, in injured hearts, they found that FSTL1 expression was missing in the epicardium and was instead present in the middle layer of the heart, the myocardium.

FSTL1 to the rescue


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)

In a eureka moment, the scientists decided to add a FSTL1 protein back to the epicardial layer of the heart, post heart injury, using the same patch system they used earlier in mice, to see whether this would promote heart tissue regeneration. Their guess was correct. FSTL1 delivery through the engineered epicardium patch system resulted in a number of beneficial effects to the heart including better function and survival, reduced scar tissue build up (a consequence of heart injury), and increased blood flow to the area of the patch.

Upon further inspection, they found that the FSTL1 epicardial patch caused heart cells to divide and proliferate. The same effect did not happen when FSTL1 is expressed in the myocardium layer of the injured heart.

To make sure their findings translated to other animal models, they studied the regenerative effects of FSTL1 in a pig model of heart injury. They applied patches infused with FSTL1 to the injured heart and as expected, observed that FSTL1 delivery improved symptoms and caused heart cells to divide.

No more heartbreak?

The authors concluded that heart injury turns off the activity of an important factor, FSTL1, in specific heart cells needed for heart regeneration. By turning on FSTL1 back on in the epicardium after injury, heart cells will receive the signal to divide and regenerate heart tissue.

Co-first author and CIRM postdoctoral scholar Ke Wei spoke to CIRM about the next steps for this study and its relevance:

Ke Wei

Co-first author, Ke Wei

In the future, we hope that our engineered epicardium patch technology can be used as a clinical platform to deliver drugs or cells to the injured heart. This strategy differs from conventional tools to treat heart attack, and may provide a novel approach in our repertoire battling heart diseases.

Thus it seems that scientists have found a potential way to patch-up a broken heart and to extend a lifeline for those suffering from heart disease. It’s comforting to know that the regenerative abilities of FSTl1 will be explored in human models and will hopefully reach clinical trials.

Ke Wei (UCSD, Sanford-Burnham-Prebys) and Vahid Serpooshan (Stanford) were co-first authors on this study. The senior authors were Daniel Bernstein (Stanford), Mark Mercola (UCSD, Sanford-Burnham-Prebys), and Pilar Ruiz-Lozano (Stanford). Both Ke Wei and Mark Mercola received CIRM funding for this study.

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CIRM-funded team traces molecular basis for differences between human and chimp face

So similar yet so different
Whenever I go to the zoo, I could easily spend my entire visit hanging out with our not-so-distant relatives, the chimpanzees. To say we humans are similar to them is quite an understatement. Sharing 96% of our DNA, chimps are more closely related to us than they are to gorillas. And when you just compare our genes – that is, the segments of DNA that contain instructions for making proteins – we’re even more indistinguishable.

Chimps and Humans: So similar yet so different

Chimps and Humans: So similar yet so different

And yet you wouldn’t mistake a human for a chimp. I mean, I do have hairy arms, but they’re not that hairy. So what accounts for our very different appearance if our genes are so similar?

To seek out answers, a CIRM-funded team at Stanford University used both human and chimp induced pluripotent stem cells (iPSCs) to derive cranial neural crest cells (CNCCs). This cell type plays a key role in shaping the overall structure of the face during the early stages of embryo development. In a report published late last week in Cell, the team found differences, not in the genes themselves, but in gene activity between the human and chimp CNCCs.

Enhancers: Volume controls for your genes
Pinpointing the differences in gene activity relied on a comparative analysis of so-called enhancer regions of human and chimp DNA. Unlike genes, the enhancer regions of DNA do not provide instructions for making proteins. Instead they dictate how much protein to make by acting like volume control knobs for specific genes. A particular volume level, or gene activity, is determined by specific combinations of chemical tags and DNA-binding proteins on an enhancer region of DNA.

Enhancers: DNA segments that act like a volume control know for gene activity (Image source: xxxx)

Enhancers: DNA segments that act like a volume control knobs for gene activity (Image source: FANTOM Project, University of Copenhagen)

The researchers used several sophisticated lab techniques to capture a snapshot of this enhancer tagging and binding in the CNCCSs. They mostly saw similarities between human and chimp enhancers but, as senior author Joanna Wysocka explains in a Stanford University press release, they did uncover some differences:

“In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development.”

PAX Humana: A genetic basis for our smaller jawline and snout?
For example, their analysis revealed that the genes PAX3 and PAX7 are associated with chimp-biased enhancer regions, and they had higher levels of activity in chimp CNCCs. These results get really intriguing once you learn a bit more about the PAX genes: other studies in mice have shown that mutations interfering with PAX function lead to mice with smaller, lower jawbones and snouts. So the lower level of PAX3/PAX7 gene activity in humans would appear to correlate with our smaller jaws and snout (mouth and nose) compared to chimps. Did that just blow your mind? How about this:

The researchers also found a variation in the enhancer region for the gene BMP4. But in this case, BMP4 was highly related to human-biased enhancer regions and had higher activity in humans compared to chimps. Previous mouse studies have shown that forcing higher levels of BMP4 specifically in CNCCs leads to shorter lower and upper jawbones, rounder skulls, and eyes positioned more to the front of the face. These changes caused by BMP4 sound an awful lot like the differences in human and chimp facial structures. It appears the Stanford group has established a terrific strategy for tracing the genetic basis for differences in humans and chimps.

So what’s next? According to Wysocka, the team is digging deeper into their data:

“We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences. It’s becoming clear that these cellular pathways can be used in many ways to affect facial shape.”

And in the bigger picture, the researchers also suggest that this “cellular anthropology” approach could also be applied to a human to human search for DNA enhancer regions that play a role in the variation between healthy and disease states.

The best scientists always want to know more

Sir Isaac Newton

Sir Isaac Newton

Some years ago I was in the Wren Library at Trinity College, Cambridge in England when I noticed a display case with a cloth over it. Being a naturally curious person, downright nosy in fact, I lifted the cloth. In the display case was a first edition of Sir Isaac Newton’s Principia Mathematica and in the margins were notes, corrections put there by Newton for the second edition.

It highlighted for me how the best scientists never stop working, never stop learning, never stop trying to improve what they do.

That came back to me when I saw a news release from ViaCyte, a company we are funding in a Phase 1 clinical trial to treat type 1 diabetes.  The news release announced results of a study showing that insulin-producing cells, created in the lab from embryonic stem cells, can not only mature but also function properly after being implanted in a capsule-like device and placed under the skin of an animal model.


Now the clinical trial we are funding with ViaCyte uses a similar, but slightly different set of cells in people. The device in the trial contains what ViaCyte calls PEC-01™ pancreatic progenitor cells. These are essentially an earlier stage of the mature pancreatic cells that our body uses to produce insulin. The hope is that when implanted in the body, the cells will mature and then behave like adult pancreatic cells, secreting insulin and other hormones to keep blood glucose levels stable and healthy.

Those cells and that device are being tested in people with type 1 diabetes right now.

Learning more

But in this study ViaCyte wanted to know if beta cells, a more mature version of the cells they are using in our trial, would also work or have any advantages over their current approach.

The good news, published in the journal Stem Cells Translational Medicine,  is that these cells did work. As they say in their news release:

“The animal study also demonstrated for the first time that when encapsulated in a device and implanted into mice, these more mature cells are capable of producing functional pancreatic beta cells. ViaCyte is also the first to show that these further differentiated cells can function in vivo following cryopreservation, a valuable process step when contemplating clinical and commercial application.”

This does not mean ViaCyte wants to change the cells it uses in the clinical trial. As President and CEO Paul Laikind, PhD, makes clear:

“For a number of reasons we believe that the pancreatic progenitor cells that are the active component of the VC01 product candidate are better suited for cell replacement therapy. However, the current work has expanded our fundamental knowledge of beta cell maturation and could lead to further advances for the field.”

And that’s what I mean about the best scientists are the ones who keeping searching, keeping looking for answers. It may not help them today, but who knows how important that work will prove in the future.