Stem Cell Roundup: Backup cells to repair damaged lungs; your unique bowels; and California Cures, 71 ways CIRM is changing the face of medicine

It’s good to have a backup plan

3D illustration of Lungs, medical concept.

Our lungs are amazing things. They take in the air we breathe and move it into our blood so that oxygen can be carried to every part of our body. They’re also surprisingly large. If you were to spread out a lung – and I have no idea why you would want to do that – it would be almost as large as a tennis court.

But lungs are also quite vulnerable organs, relying on a thin layer of epithelial cells to protect them from harmful materials in the air. If those materials damage the lungs our body calls in local stem cells to repair the injury.

Now researchers at the University of Iowa have identified a new group of stem cells, called glandular myoepithelial cells (MECs), that also appear to play an important role in repairing injuries in the lungs.

These MECs seem to be a kind of “reserve” stem cell, waiting around until they are needed and then able to spring into action and develop into new replacement cells in the lungs.

In a news release study author Preston Anderson, said these cells could help develop new approaches to lung regeneration:

“We demonstrated that MECs can self-renew and differentiate into seven distinct cell types in the airway. No other cell type in the lung has been identified with this much stem cell plasticity.”

The study is published in Cell Stem Cell.

Your bowels are unique

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Not to worry, that’s a plastic model of  a bowel

If you are eating as you read this, you should either put your food down or skip this item for now. A new study on bowel cancer says that every tumor is unique and every cell within that tumor is also genetically unique.

Researchers in the UK and Netherlands took samples of normal bowel tissue and cancerous bowel tissue from three people with colorectal cancer. They then grew these in the labs and turned them into mini 3D organoids, so they could study them in greater detail.

In the study, published in the journal Nature, the researchers say they found that tumor cells, not surprisingly, had many more mutations than normal cells, and that not only was each bowel cancer genetically different from each other, but that each cell they studied within that cancer was also different.

In a news release, Prof Sir Mike Stratton, joint corresponding author on the paper from the Wellcome Sanger Institute, said:

“This study gives us fundamental knowledge on the way cancers arise. By studying the patterns of mutations from individual healthy and tumour cells, we can learn what mutational processes have occurred, and then look to see what has caused them. Extending our knowledge on the origin of these processes could help us discover new risk factors to reduce the incidence of cancer and could also put us in a better position to create drugs to target cancer-specific mutational processes directly.”

California Cures: a great title for a great book about CIRM

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CIRM Board Chair Jonathan Thomas (L) and Don Reed

One of the first people I met when I started working at CIRM was Don Reed. He impressed me then with his indefatigable enthusiasm, energy and positive outlook on life. Six years later he is still impressing me.

Don has just completed his second book on stem cell research charting the work of CIRM. It’s called “California Cures: How the California Stem Cell Research Program is Fighting Your Incurable Disease”. It’s a terrific read combining stories about stem cell research with true tales about Al Jolson, Enrico Caruso and how a dolphin named Ernestine burst Don’s ear drum.

On his website, Stem Cell Battles, Don describes CIRM as a “scrappy little stage agency” – I love that – and says:

“No one can predict the pace of science, nor say when cures will come; but California is bringing the fight. Above all, “California Cures” is a call for action. Washington may argue about the expense of health care (and who will get it), but California works to bring down the mountain of medical debt: stem cell therapies to ease suffering and save lives. We have the momentum. We dare not stop short. Chronic disease threatens everyone — we are fighting for your family, and mine!”

 

Stem cell stories that caught our eye: insights into stem cell biology through telomeres, reprogramming and lung disease

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.

Telomeres and stem cell stability: too much of a good thing

Just like those plastic tips at the end of shoelaces (fun fact: they’re called aglets), telomeres form a protective cap on the end of chromosomes. Because of the way DNA replication works, the telomeres shorten each time a cell divides. Trim away enough of the telomere over time and, like a frayed shoelace, the chromosomes become unstable and an easy target for damage which eventually leads to cell death.

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Telomeres (white dots) form a protective cap on chromsomes (gray). (Wikimedia) 

Stem cells are unique in that they contain an enzyme called telomerase that lengthens telomeres. Telomerase activity and telomere lengthening are critical for a stem cell’s ability to maintain virtually limitless cell divisions. So you’d assume the longer the telomere, the more stable the cell. But Salk Institute scientists reported this week that too much telomere can be just as bad, if not worse, than too little.

The CIRM-funded work, which was published in Nature Structural & Molecular Biology, used genetic engineering to artificially vary telomerase activity in human embryonic stem cells. Cells with low telomerase activity had shorter telomeres and died. This result wasn’t a surprise since the short telomeres-cell death observation has been well documented. Based on those results, the team was expecting cells with boosted telomerase activity and, in turn, extended telomeres would be especially stable. But that’s not what happened as senior author Jan Karlseder mentioned in a Salk press release:

“We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism.”

The researchers also examined induced pluripotent stem (iPS) cells in the study and found that the cells contain “footprints” of telomere trimming. So the team is in a position to study how a cell’s telomere history relates to how well it can be reprogrammed into iPS cells. First author Teresa Rivera pointed out the big picture significance of this finding:

“Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine.”

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Jan Karlseder and Teresa Rivera

Lego set of gene activators takes trial and error out of cellular reprogramming

To convert one cell type into another, stem cell researchers rely on educated guesses and a lot of trial and error. In fact, that’s how Shinya Yamanaka identified the four Yamanaka Factors which, when inserted into a skin cell, reprogram it into the embryonic stem cell-like state of an iPS cell. That ground-breaking discovery ten years ago has opened the way for researchers worldwide to specialize iPS cells into all sorts of cell types from nerve cells to liver cells. While some cell types are easy to generate this way, others are much more difficult.

Reporting this week in PNAS, a University of Wisconsin–Madison research team has developed a nifty systematic, high-throughput method for identifying the factors necessary to convert a cell from one type to another. Their strategy promises to free researchers from the costly and time consuming trial and error approach still in use today.

The centerpiece of their method is artificial transcription factors (ATFs). Now, natural transcription factors – Yamanaka’s Factors are examples – are proteins that bind DNA and activate or silence genes. Their impact on gene activity, in turn, can have a cascading effects on other genes and proteins ultimately causing, say a stem cell, to start making muscle proteins and turn into a muscle cell.

Transcription factors are very modular proteins – one part is responsible for binding DNA, another part for affecting gene activity and other parts that bind to other proteins. The ATFs generated in this study are like lego versions of natural transcription factors – each are constructed from combinations of different transcription factor parts. The team made nearly 3 million different ATFs.

As a proof of principle, the researchers tried reproducing Yamanaka’s original, groundbreaking iPS cell experiment. They inserted the ATFs into skin cells that already had 3 of the 4 Yamanaka factors, they left out Oct4. They successfully generated iPS with this approach and then went back and studied the makeup of the ATFs that had caused cells to reprogram into iPS cells. Senior author Aseem Ansari gave a great analogy in a university press release:

“Imagine you have millions of keys and only a unique key or combination of keys can turn a motor on. We test all those keys in parallel and when we see the motor fire up, we go back to see exactly which key switched it on.”

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Micrograph of induced pluripotent stem cells generated from artificial transcription factors. The cells express green fluorescent protein after a key gene known as Oct4 is activated. (ASUKA EGUCHI/UW-MADISON)

The analysis showed that these ATFs had stimulated gene activity cascades which didn’t directly involve Oct4 but yet ultimately activated it. This finding is important because it suggests that future cell conversion experiments could uncover some not so obvious cell fate pathways. Ansari explains this point further:

“It’s a way to induce cell fate conversions without having to know what genes might be important because we are able to test so many by using an unbiased library of molecules that can search nearly every corner of the genome.”

This sort of brute force method to accelerate research discoveries is music to our ears at CIRM because it ultimately could lead to therapies faster.

Search for clues to treat deadly lung disease

When researchers don’t understand what causes a particular disease, a typical strategy is to compare gene activity in diseased vs healthy cells and identify important differences. Those differences may lead to potential paths to developing a therapy. That’s the approach a collaborative team from Cincinnati Children’s Hospital and Cedars-Sinai Medical took to tackle idiopathic pulmonary fibrosis (IPF).

IPF is a chronic lung disease which causes scarring, or fibrosis, in the air sacs of the lung. This is the spot where oxygen is taken up by tiny blood vessels that surround the air sacs. With fibrosis, the air sacs stiffen and thicken and as a result less oxygen gets diffused into the blood and starves the body of oxygen.  IPF can lead to death within 2 to 5 years after diagnosis. Unfortunately, no cures exist and the cause is unknown, or idiopathic.

(Wikimedia)

(Wikimedia)

The transfer of oxygen from air sacs to blood vessels is an intricate one with many cell types involved. So pinpointing what goes wrong in IPF at a cellular and molecular level has proved difficult. In the current study, the scientists, for the first time, collected gene sequencing data from single cells from healthy and diseased lungs. This way, a precise cell by cell analysis of gene activity was possible.

One set of gene activity patterns found in healthy sample were connected to proper formation of a particular type of air sac cell called the aveolar type 2 lung cell. Other gene patterns were linked to abnormal IPF cell types. With this data in hand, the researchers can further investigate the role of these genes in IPF which may open up new therapy approaches to this deadly disease.

The study funded in part by CIRM was published this week in Journal of Clinical Investigation Insight and a press release about the study was picked up by PR Newswire.

Failed stem cells may cause deadly lung disease

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Breathing is something we take for granted. It’s automatic. We don’t need to think about it. But for people with pulmonary fibrosis, breathing is something that is always on their minds.

Pulmonary fibrosis (PF) is a disease where the tissue in your lungs becomes thick and stiff, even scarred, making it difficult to breathe. It can be a frightening experience; and it doesn’t just affect your lungs.

Because your lungs don’t work properly they aren’t able to move as much oxygen as you need into your bloodstream, and that can have an impact on all your other organs, such as your brain and heart. There are some treatments but no cures, in large part because we didn’t know the cause of the disease. Many patients with PF live only 3-5 years after diagnosis.

Now a new CIRM-funded study from researchers at Cedars-Sinai has uncovered clues as to the cause of the disease, and that in turn could pave the way to new treatments.

The study, published in the journal Nature, found that a class of stem cells in the lung, called AEC2s, are responsible for helping repair damage caused by things such as pollution or infection. People who have PF have far fewer of these AEC2 cells, and those cells also had a much lower concentration of a chemical substance called hyaluronan, which is essential for repair damaged tissue.

They tested this theory with laboratory mice and found that by removing hyaluronan the mice developed thick scarring in their lungs.

In a news release from Cedars-Sinai Carol Liang, the study’s first author, said knowing the cause of the problem may help identify potential solutions:

“These findings are the first published evidence that idiopathic pulmonary fibrosis is primarily a disease of AEC2 stem cell failure. In further studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches.”

Knowing that a problem with AEC2 cells causes PF means the researchers can now start testing different medications to see which ones might help boost production of replacement AEC2 cells, or help protect those still functioning.

Stem cell agency funds clinical trials in three life-threatening conditions

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A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

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

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Stem cell stories that caught our eye: diabetes drug hits cancer, video stem cell tracker and quick n’ easy stem cells for fatal lung disease


The chemical structure of Metformin (Image source: WikiMedia Commons)

The chemical structure of Metformin (Image source: WikiMedia Commons)

Teaching an old drug new tricks.
One the quickest way to get a drug to market is to find one that’s already been FDA approved for other diseases. Reporting this week in Cell Metabolism, researchers from London and Madrid identified the mechanisms that enable the anti-diabetic drug, metformin, to kill pancreatic cancer stem cells (PanCSCs).

Though they make up a tiny portion of a tumor, cancer stem cells (CSCs) are thought to lie dormant most of the time. As a result, they evade chemotherapy only to later revive the tumor and cause relapse. So, the hypothesis goes, target and kill the CSCs and you’ll eradicate the cancer.

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Mitochondria – a cell’s power station (image source: WikiMedia Commons)

While most cancer cells produce their energy needs without the use of oxygen, the team found that PanCSCs use oxygen-dependent energy production that occurs in a cell structure called the mitochondria. Because metformin blocks key components of the mitochondria’s energy factory, the drug essentially shuts down power to the PanCSCs leading to cell death.

The PanCSCs still have another trick up their proverbial sleeves: some switch over to a mitochondria-independent form of energy production so the metformin becomes useless against the PanCSCs. However, by tweaking the levels of two proteins, the researchers forced the PanCSCs to only use the mitochondria for energy production, which restored metformin’s cancer-killing ways.

Pancreatic cancer has very poor survival rates with very limited treatment options. Let’s hope this work leads to alternatives for patients and their doctors.

It’s all about location, location, location. Or is it?
We’ve written numerous times at the Stem Cellar about the importance of a stem cell’s “neighborhood” for determining the cell type into which it will eventually specialize. But a study published this week in Stem Cell Reports put the role of a cell’s surroundings somewhat into question.

A research team at Drexel University in Philadelphia compared stem cells in the back of the brain – an area that interprets visual information – with stem cells in the front of the brain – an area responsible for controlling movement. A fundamental question about brain development is how these areas form very different structures. Are the stem cells in each part of the brain already programmed to take on different fates or are they blank slates which rely on protein signals in the local environment to determine the type of nerve cell they become?

To chip away at this question, the team isolated mouse stem cells from the back and the front on the brain. Each set was grown in the lab using the same nutrients and conditions. You might have guessed the stem cells would behave the same but that’s not what happened. Compared to the stem cells from the back of the brain, the front brain stem cells gave rise to smaller daughter cells that divided more slowly. This suggests these brain stem cells already have some built-in properties that set them apart.

The methods used in the study are as fascinating as the results themselves. The team developed a time-lapse cell-tracking system from scratch that, with minimal human intervention, tags individual daughter cells and analyzes their fate as they grow, move and specialize on the petri dish. In the movie below, Professor Andrew Cohen, one of the authors who helped design the web-based software, succinctly describes the work. Also this movie of the tracking system in action is stunning.

Kudos to the team for making the software and their data set open access. There’s no doubt this technology will lead to important new discoveries.

Quick and easy stem cells to fight deadly lung disease
Lung disease is the 3rd deadliest disease in the U.S. It afflicts 33 million people and accounts for one in six deaths. One of those diseases is Idiopathic Pulmonary Fibrosis (IPF), an incurable disease that causes scarring and thickening of the lungs and makes breathing more and more labored. People often succumb to the disease within 3 to 5 years of their diagnosis. Use of lung stem cells to replace and heal damaged tissue is a promising therapeutic strategy for IPF.

Red and green indicate lung stem cells within a spheroid. (Image credit: Henry et al. Stem Cells Trans Med September 2015-0062)

Red and green indicate lung stem cells within a spheroid. (Image credit: Henry et al. Stem Cells Trans Med September 2015-0062)

This week, a research team from North Carolina State University reported in Stem Cells Translational Medicine on a quick and easy method for growing large amounts of lung stem cells from healthy lung tissue. The typical process of harvesting the tissue, sorting the individual lung cells, and growing the cells on petri dishes can be costly and time-consuming.

Instead, the NCSU team grew the human lung stem cells in three dimensional spheres containing multiple cell types and allowed them to float in liquid nutrients. The lung stem cells are at the center of the sphere surrounded by support cells. This method better resembles the natural cellular environment of the stem cells compared to a flat homogenous lawn of cells in a petri dish.

When introduced intravenously into mice with IPF-like symptoms, these lung spheroids reduced lung scarring and inflammation, nearly matching the animals without IPF. And in a head-to-head comparison, the lung spheroids were more effective than fat-derived mesenchymal stem cells, another proposed cell source for treating lung disease. Alas, humans are not mice and more studies are necessary to reach the ultimate goal of treating IPF patients. But I’m excited about this team’s progress and look forward to hearing more from them.

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