Stem cell stories that caught our eye: new baldness treatments?, novel lung stem cells, and giraffe stem cells

Novel immune system/stem cell interaction may lead to better treatments for baldness. When one thinks of the immune system it’s usually in terms of the body’s ability to fight off a bad cold or flu virus. But a team of UCSF researchers this week report in Cell that a particular cell of the immune system is key to instructing stem cells to maintain hair growth. Their results suggest that the loss of these immune cells, called regulatory T cells (Tregs for short), may be the cause of baldness seen in alopecia areata, a common autoimmune disorder and may even play a role in male pattern baldness.

Alopecia, a common autoimmune disorder that causes baldness. Image: Shutterstock

While most cells of the immune system recognize and kill foreign or dysfunctional cells in our bodies, Tregs act to subdue those cells to avoid collateral damage to perfectly healthy cells. If Tregs become impaired, it can lead to autoimmune disorders in which the body attacks itself.

The UCSF team had previously shown that Tregs allow microorganisms that are beneficial to skin health in mice to avoid the grasp of the immune system. In follow up studies they intended to examine what happens to skin health when Treg cells were inhibited in the skin of the mice. The procedure required shaving away small patches of hair to allow observation of the skin. Over the course of the experiment, the scientists notice something very curious. Team lead Dr. Michael Rosenblum recalled what they saw in a UCSF press release:

“We quickly noticed that the shaved patches of hair never grew back, and we thought, ‘Hmm, now that’s interesting. We realized we had to delve into this further.”

That delving showed that Tregs are located next to hair follicle stem cells. And during the hair growth, the Tregs grow in number and surround the stem cells. Further examination, found that Tregs trigger the stem cells through direct cell to cell interactions. These mechanisms are different than those used for their immune system-inhibiting function.

With these new insights, Dr. Rosenblum hopes this new-found role for Tregs in hair growth may lead to better treatments for Alopecia, one of the most common forms of autoimmune disease.

Novel lung stem cells bring new insights into poorly understood chronic lung disease. Pulmonary fibrosis is a chronic lung disease that’s characterized by scarring and changes in the structure of tiny blood vessels, or microvessels, within lungs. This so-called “remodeling” of lung tissue hampers the transfer of oxygen from the lung to the blood leading to dangerous symptoms like shortness of breath. Unfortunately, the cause of most cases of pulmonary fibrosis is not understood.

This week, Vanderbilt University Medical Center researchers report in the Journal of Clinical Investigation the identification of a new type of lung stem cell that may play a role in lung remodeling.

Susan Majka and Christa Gaskill, and colleagues are studying certain lung stem cells that likely contribute to the pathobiology of chronic lung diseases.  Photo by: Susan Urmy

Up until now, the cells that make up the microvessels were thought to contribute to the detrimental changes to lung tissue in pulmonary fibrosis or other chronic lung diseases. But the Vanderbilt team wasn’t convinced since these microvessel cells were already fully matured and wouldn’t have the ability to carry out the lung remodeling functions.

They had previously isolated stem cells from both mouse and human lung tissue located near microvessels. In this study, they tracked these mesenchymal progenitor cells (MPCs) in normal and disease inducing scenarios. The team’s leader, Dr. Susan Majka, summarized the results of this part of the study in a press release:

“When these cells are abnormal, animals develop vasculopathy — a loss of structure in the microvessels and subsequently the lung. They lose the surfaces for gas exchange.”

The team went on to find differences in gene activity in MPCs from healthy versus diseased lungs. They hope to exploit these differences to identify molecules that would provide early warnings of the disease. Dr. Majka explains the importance of these “biomarkers”:

“With pulmonary vascular diseases, by the time a patient has symptoms, there’s already major damage to the microvasculature. Using new biomarkers to detect the disease before symptoms arise would allow for earlier treatment, which could be effective at decreasing progression or even reversing the disease process.”

The happy stem cell story of Mahali the giraffe. We leave you this week with a feel-good story about Mahali, a 14-year old giraffe at the Cheyenne Mountain Zoo in Colorado. Mahali had suffered from chronic arthritis in his front left leg. As a result, he could not move well and was kept isolated from his herd.

Giraffes at Cheyenne Mountain Zoo. Photo: Denver Post

The zoo’s head veterinarian, Dr. Liza Dadone, decided to try a stem cell therapy procedure to bring Mahali some relief and a better quality of life. It’s the first time such a treatment would be performed on a giraffe. With the help of doctors at Colorado State University’s James L. Voss Veterinary Teaching Hospital, 100 million stem cells grown from Mahali’s blood were injected into his arthritic leg.

Before treatment, thermograph shows inflammation (red/yellow) in Mahali’s left front foot (seen at far right of each image); after treatment inflammation resolved (blue/green). Photos: Cheyenne Mountain Zoo

In a written statement to the Colorado Gazette, Dr. Dadone summarized the positive outcome:

“Prior to the procedure, he was favoring his left front leg and would lift that foot off the ground almost once per minute. Since then, Mahali is no longer constantly lifting his left front leg off the ground and has resumed cooperating for hoof care. A few weeks ago, he returned to life with his herd, including yard access. On the thermogram, the marked inflammation up the leg has mostly resolved.”

Now, Dr. Dadone made sure to state that other treatments and medicine were given to Mahali in addition to the stem cell therapy. So, it’s not totally clear to what extent the stem cells contributed to Mahali’s recovery. Maybe future patients will receive stem cells alone to be sure. But for now, we’re just happy for Mahali’s new lease on life.

New target for defeating breast cancer stem cells uncovered

Stashed away in most of your tissues and organs lie small populations of adult stem cells. They help keep our bodies functioning properly by replenishing dying or damaged cells. Their ability to make more copies of themselves, as needed, ensures that there’s always an adequate supply set aside. But this very same self-renewing, life-sustaining property of adult stem cells is deadly in the hands of cancer stem cells. Also called tumor-initiating cells, cancer stem cells sustain tumor growth even after chemotherapy and are thought to be a primary cause of cancer relapse.

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Microscopic image of normal mouse mammary ducts. Mammary stem cells are found among basal cells (green). Image courtesy of Toni Celià-Terrassa and Yibin Kang, Princeton University

By studying adult and cancer stem cells side-by-side, Princeton researchers report this week in Nature Cell Biology that they’ve uncovered a common function in both cells types that not only helps explain an adult stem cell’s self-renewing ability but also points to new therapeutic approaches to targeting breast cancer stem cells.

Both adult and cancer stem cells continually resist signals from their environment that encourage them to specialize, or differentiate, into a particular cell type. Once specialized, the cells lose their ability to self-renew and will eventually die off. Now, if all the adult stem cells in an organ followed that instruction, they would eventually become depleted and the organ would lose the ability to repair itself. The same holds true for cancer stem cells which actually would be a good thing since it would lead to the tumor’s death.

The Princeton team first identified a molecule called miR-199a that allows mammary (breast) stem cells to resist differentiation signals by directly blocking the production of a protein called LCOR. Artificially boosting the amount of miR-199a led to a decrease in LCOR levels and an increase in stem cell function. But when LCOR levels were increased, mammary stem cell function was restricted.

The researchers then turned their attention to breast cancer stem cells and found the same miR-199a/LCOR function at work. In a similar fashion, boosting miR-199a levels enhanced cancer stem cell function and increased tumor formation while increasing LCOR restricted the tumor-forming ability of the breast cancer stem cells.

These lab results also matched up with tissue samples taken from breast cancer patients. High miR-199a levels in the samples correlated with low patient survival rates. But those with high levels of LCOR showed a better prognosis.

It turns out that cells in our immune system are responsible for boosting LCOR in mammary and breast cancer stem cells by releasing a protein called interferon alpha. So the presence of interferon alpha nudges mammary stem cells to mature into mammary gland cells and inhibits breast cancer stems from forming tumors. But in the presence of elevated miR-199a levels, mammary and breast cancer stem cells are protected and maintain their numbers by deactivating the interferon alpha/LCOR signal.

If you’re still with me, these results point to miR-199a as a promising target for restoring interferon-alpha’s cancer interfering properties. Team leader Dr. Yibin Kang highlighted this possibility in a Princeton University press release:

“Interferons have been widely used for the treatment of multiple cancer types. These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”

Stem cell stories that caught our eye: lab-grown blood stem cells and puffer fish have the same teeth stem cells as humans

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.

Scientists finally grow blood stem cells in the lab!

Two exciting stem cell studies broke through the politics-dominated headlines this week. Both studies, published in the journal Nature, demonstrated that human hematopoietic or blood stem cells can be grown in the lab.

This news is a big deal because scientists have yet to make bonafide blood stem cells from pluripotent stem cells or other human cells. These stem cells not only create all the cells in our blood and immune systems, but also can be used to develop therapies for patients with blood cancers and genetic blood disorders.

But to do these experiments, you need a substantial source of blood stem cells – something that has eluded scientists for decades. That’s where these two studies come to the rescue. One study was spearheaded by George Daley at the Boston Children’s Hospital in Massachusetts and the other was led by Shahin Rafii at the Weill Cornell Medical College in New York City.

Researchers have made blood stem cells and progenitor cells from pluripotent stem cells. Credit: Steve Gschmeissner Getty Images

George Daley and his team developed a strategy that matured human induced pluripotent stem cells (iPS cells) into blood-forming stem and progenitor cells. It’s a two-step process that first uses a cocktail of chemicals to make hemogenic endothelium, the embryonic tissue that generates blood stem cells. The second step involved treating these intermediate cells with a combination of seven transcription factors that directed them towards a blood stem cell fate.

These modified human blood stem cells were then transplanted into mice where they developed into blood stem cells that produced blood and immune cells. First author on the study, Ryohichi Sugimura, explained the applications that their technology could be used for in a Boston Children’s Hospital news release,

“This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.”

The second study by Shahin Rafii and his team at Cornell used a different strategy to generate blood-forming stem cells. Instead of genetically manipulating iPS cells, they selected a more mature cell type to directly reprogram into blood stem cells. Using four transcription factors, they successfully reprogrammed mouse endothelial cells, which line the insides of blood vessels, into blood-forming stem cells that repopulated the blood and immune systems of irradiated mice.

Raffii believe his method is simpler and more efficient than Daley’s. In coverage by Nature News, he commented,

“Using the most efficient method to generate stem cells matters because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumors if they are implanted into people.”

To play devil’s advocate, Daley’s technique might appeal more to some because the starting source of iPS cells is much easier to obtain and culture in the lab than endothelial cells that have to be extracted from the blood vessels of animals or people. Furthermore, Daley argued that his team’s method could “be made more efficient, and [is] less likely to spur tumor growth and other abnormalities in modified cells.”

The Nature News article compares the achievements of both studies and concluded,

“Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells.”

 

Humans and puffer fish have the same tooth-making stem cells.

Here’s a fun fact for your next blind date: humans and puffer fish share the same genes that are responsible for making teeth. Scientists from the University of Sheffield in England discovered that the stem cells that make teeth in puffer fish are the same stem cells that make the pearly whites in humans. Their work was published in the journal PNAS earlier this week.

Puffer fish. Photo by pingpogz on Flickr.

But if you look at this puffer fish, you’ll see a dramatic difference between its smile and ours – their teeth look more like a beak. Research has shown that the tooth-forming stem cells in puffer fish produce tooth plates that form a beak-like structure, which helps them crush and consume their prey.

So why is this shared evolution between humans and puffer fish important when our teeth look and function so differently? The scientists behind this research believe that studying the pufferfish could unearth answers about tooth loss in humans. The lead author on the study, Dr. Gareth Fraser, concluded in coverage by Phys.org,

“Our study questioned how pufferfish make a beak and now we’ve discovered the stem cells responsible and the genes that govern this process of continuous regeneration. These are also involved in general vertebrate tooth regeneration, including in humans. The fact that all vertebrates regenerate their teeth in the same way with a set of conserved stem cells means that we can use these studies in more obscure fishes to provide clues to how we can address questions of tooth loss in humans.”

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?

math

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.

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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.”

Pleasant surprise reveals molecular insights about graying and balding hair

A lesson that every lab researcher learns early in their career is that experiments often don’t give you the results you expect. But that’s not always a bad thing. Sometimes surprising results can lead to new insights or can even steer your research in completely new, exciting directions.

That’s what happened to scientists at the University of Texas Southwestern Medical Center. What started out as a project to better understand a genetic disorder – called neurofibromatosis – that causes benign tumor growth on nerve cells, turned into new discoveries about the cellular basis for graying and balding hair – at least in mice.

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Starting at 30 days after birth (P30, upper right picture), mouse lacking the SCF gene (top mouse in each picture) gradually loses hair pigment while hair color of control mouse remains unchanged. Photo: Fig 1A, Genes Dev. 2017 May 2.

The team was studying neurofibromatosis in mouse cells that produce Krox20, a protein which plays a role in the development of nerve cells. Krox20, in turn, stimulates the production of another protein called Stem Cell Factor (SCF). With some genetic engineering tricks, a mouse strain lacking SCF specifically in these Krox20-producing cells was bred to uncover SCF’s impact on neurofibromatosis.

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Hair production and pigmentation occurs in hair follicle. Image: Shutterstock

But the researchers couldn’t help noticing something else: as reported in Genes and Development, just a month after birth, all 20 mice had graying fur and by nine months, their fur was completely white. Another set of mice was bred to lack Krox20-producing cells. The resulting animals completely lacked hair. Further experiments determined that the Krox20-producing cells in the hair follicle were stem cell-like progenitor cells that give rise to the cells responsible for hair production and pigmentation.

Piecing the data together, the researchers created a visual model of the hair follicle in which the progenitor cells maintain a steady supply of hair-producing cells with Krox20 playing a critical role. And the SCF produced by those cells allows the uptake of hair pigment called melanin, from nearby melanocyte cells also found in the hair follicle.

This model suggests that as we age, something causes a reduction in SCF in the hair follicle which leads to graying hair. The model also suggests that thinning hair, which is quite common in both men and women, is triggered by a reduction in the number of progenitor cells in the follicle.

Given that the treatment of hair loss and graying are multi-billion dollar industries, it’s no surprise that this story got a lot of attention in the press. Based on the titles of some of those news articles, you’d think new, game-changing hair products are just around the corner. In reality, this research is at a very early stage and will require many years of follow up experiments to figure out if and how commercialization of the technology is possible.

Still, as lead scientist Dr. Lu Le explains in a press release, the team has a vision for what their ultimate goal might look like:

“With this knowledge, we hope in the future to create a topical compound or to safely deliver the necessary gene to hair follicles to correct these cosmetic problems.”

 

Keeping intestinal stem cells in their prime

Gut stem cells (green) in the small intestine of a mouse.

The average length of the human gut is 25 feet long. That’s equivalent to four really tall people or five really short people lined up head to toe. Intestinal stem cells have the fun job of regenerating and replacing ALL the cells that line the gut. Therefore, it’s important for these stem cells to be able to self-renew, a process that replenishes the stem cell population. If this important biological process is disrupted, the intestine is at risk for diseases like inflammatory bowel disease and cancer.

This week, Stanford Medicine researchers published new findings about the biological processes responsible for regulating the regenerative capacity of intestinal stem cells. Their work, which was partially funded by CIRM, was published in the journal Nature.

Priming gut stem cells to self-renew

Scientists know that the self-renewal of intestinal stem cells is very important for a happy, functioning gut, but the nuances of what molecules and signaling pathways regulate this process have yet to be figured out. The Stanford team, led by senior author and Stanford Professor Dr. Calvin Kuo, studied two signaling pathways, Wnt and R-Spondin, that are involved in the self-renewal of intestinal stem cells in mice.

Dr. Calvin Kuo, Stanford Medicine.

“The cascade of events comprising the Wnt signaling pathway is crucial to stem cell self-renewal,” Dr. Kuo explained in an email exchange. “The Wnt pathway can be induced by either hormones classified as “Wnts” or “R-spondins”.  However, it is not known if Wnts or R-spondins cooperate to induce Wnt signaling, and if these Wnts and R-spondins have distinct functions or if they can mutually substitute for each other.   We explored how Wnts and R-spondins might cooperate to regulate intestinal stem cells – which are extremely active and regenerate the 25-foot lining of the human intestine every week.”

The team used different reagents to activate or block Wnt or R-spondin signaling and monitored the effects on intestinal stem cells. They found that both were important for the self-renewal of intestinal stem cells, but that they played different roles.

“Our work revealed that Wnts and R-spondins are not equivalent and that they have very distinct functions even though they both trigger the Wnt signaling cascade,” said Dr. Kuo. “Both Wnts and R-spondins are required to maintain intestinal stem cells.  However, Wnts perform more of a subservient “priming” function, where they prepare intestinal stem cells for the action of R-spondin, which is the active catalyst for inducing intestinal stem cells to divide.”

The authors believe that this multi-step regulation, involving priming and self-renewal factors could apply to stem cell systems in other organs and tissues in the body. Some of the researchers on this study including Dr. Kuo are pursuing this idea through a new company called Surrozen, which produces artificial bioengineered Wnt molecules that don’t require activation like natural Wnt molecules. These Wnt molecules were used in the current study and are explained in more detail in a separate Nature article published at the same time.

The company believes that artificial Wnts will be useful for understanding stem cell biology and potentially for therapeutic applications. Dr. Kuo explained,

“The new surrogate Wnts are easily produced and can circulate in the bloodstream, unlike natural Wnts.  There may be medical applications of these bioengineered Wnt surrogates in stimulating various stem cell compartments of the body, given the wide range of stem cells that are governed by natural Wnts.”

jCyte gets FDA go-ahead for Fast Track review process of Retinitis Pigmentosa stem cell therapy

21 century cures

When the US Congress approved, and President Obama signed into law, the 21st Century Cures Act last year there was guarded optimism that this would help create a more efficient and streamlined, but no less safe, approval process for the most promising stem cell therapies.

Even so many people took a wait and see approach, wanting a sign that the Food and Drug Administration (FDA) would follow the recommendations of the Act rather than just pay lip service to it.

This week we saw encouraging signs that the FDA is serious when it granted Regenerative Medicine Advanced Therapy (RMAT) status to the CIRM-funded jCyte clinical trial for a rare form of blindness. This is a big deal because RMAT seeks to accelerate approval for stem cell therapies that demonstrate they can help patients with unmet medical needs.

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jCyte co-founder Dr. Henry Klassen

jCyte’s work is targeting retinitis pigmentosa (RP), a genetic disease that slowly destroys the cells in the retina, the part of the eye that converts light into electrical signals which the brain then interprets as vision. At first people with RP lose their night and peripheral vision, then the cells that help us see faces and distinguish colors are damaged. RP usually strikes people in their teens and, by the time they are 40, many people are legally blind.

jCyte’s jCell therapy uses what are called retinal progenitor cells, injected into the eye, which then release protective factors to help repair and rescue diseased retinal cells. The hope is this will stop the disease’s progression and even restore some vision to people with RP.

Dr. Henry Klassen, jCyte’s co-founder and a professor at UC Irvine, was understandably delighted by the designation. In a news release, he said:

“This is uplifting news for patients with RP. At this point, there are no therapies that can help them avoid blindness. We look forward to working with the FDA to speed up the clinical development of jCell.”

FDA

On the FDA’s blog – yes they do have one – it says researchers:

“May obtain the RMAT designation for their drug product if the drug is intended to treat serious or life-threatening diseases or conditions and if there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for that disease or condition. Sponsors of RMAT-designated products are eligible for increased and earlier interactions with the FDA, similar to those interactions available to sponsors of breakthrough-designated therapies. In addition, they may be eligible for priority review and accelerated approval.”

Paul Bresge

jCyte CEO Paul Bresge

jCyte is one of the first to get this designation, a clear testimony to the quality of the work done by Dr. Klassen and his team. jCyte CEO Paul Bresge says it may help speed up their ability to get this treatment to patients.

 

“We are gratified by the FDA’s interest in the therapeutic potential of jCell and greatly appreciate their decision to provide extra support. We are seeing a lot of momentum with this therapy. Because it is well-tolerated and easy to administer, progress has been rapid. I feel a growing sense of excitement among patients and clinicians. We look forward to getting this critical therapy over the finish line as quickly as possible.”

Regular readers of this blog will already be familiar with the story of Rosie Barrero, one of the first group of people with RP who got the jCell therapy. Rosie says it has helped restore some vision to the point where she is now able to read notes she wrote ten years ago, distinguish colors and, best of all, see the faces of her children.

RMAT is no guarantee the therapy will be successful. But if the treatment continues to show promise, and is safe, it could mean faster access to a potentially life-changing therapy, one that could ultimately rescue many people from a lifetime of living in the dark.

 

 

Stem cell stories that caught our eye: developing the nervous system, aging stem cells and identical twins not so identical

Here are the stem cell stories that caught our eye this week. Enjoy!

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

Could revving up stem cells help senior citizens heal as fast as high school seniors?

All physicians, especially surgeons, sport medicine doctors, and military medical corps share a similar wish: to able to speed up the healing process for their patients’ incisions and injuries. Data published this week in Cell Reports may one day fulfill that wish. The study – reported by a Stanford University research team – pinpoints a single protein that revs up stem cells in the body, enabling them to repair tissue at a quicker rate.

Screen Shot 2017-04-19 at 5.37.38 PM

Muscle fibers (dark areas surrounding by green circles) are larger in mice injected with HGFA protein (right panel) compared to untreated mice (left panel), an indication of faster healing after muscle injury.
(Image: Cell Reports 19 (3) p. 479-486, fig 3C)

Most of the time, adult stem cells in the body keep to themselves and rarely divide. This calmness helps preserve this important, small pool of cells and avoids unnecessary mutations that may happen whenever DNA is copied during cell division.

To respond to injury, stem cells must be primed by dividing one time, which is a very slow process and can take several days. Once in this “alert” state, the stem cells are poised to start dividing much faster and help repair damaged tissue. The Stanford team, led by Dr. Thomas Rando, aimed to track down the signals that are responsible for this priming process with the hope of developing drugs that could help jump-start the healing process.

Super healing serum: it’s not just in video games
The team collected blood serum from mice two days after the animals had been subjected to a muscle injury (the mice were placed under anesthesia during the procedure and given pain medication afterwards). When that “injured” blood was injected into a different set of mice, their muscle stem cells became primed much faster than mice injected with “uninjured” blood.

“Clearly, blood from the injured animal contains a factor that alerts the stem cells,” said Rando in a press release. “We wanted to know, what is it in the blood that is doing this?”

 

A deeper examination of the priming process zeroed in on a muscle stem cell signal that is turned on by a protein in the blood called hepatocyte growth factor (HGF). So, it seemed likely that HGF was the protein that they had been looking for. But, to their surprise, there were no differences in the amount of HGF found in blood from injured and uninjured mice.

HGFA: the holy grail of healing?
It turns out, though, that HGF must first be chopped in two by an enzyme called HGFA to become active. When the team went back and examined the injured and uninjured blood, they found that it was HGFA which showed a difference: it was more active in the injured blood.

To show that HGFA was directly involved in stimulating tissue repair, the team injected mice with the enzyme two days before the muscle injury procedure. Twenty days post injury, the mice injected with HGFA had regenerated larger muscle fibers compared to untreated mice. Even more telling, nine days after the HGFA treatment, the mice had better recovery in terms of their wheel running activity compared to untreated mice.

To mimic tissue repair after a surgery incision, the team also looked at the impact of HGFA on skin wound healing. Like the muscle injury results, injecting animals with HGFA two days before creating a skin injury led to better wound healing compared to untreated mice. Even the hair that had been shaved at the surgical site grew back faster. First author Dr. Joseph Rodgers, now at USC, summed up the clinical implications of these results :

“Our research shows that by priming the body before an injury you can speed the process of tissue repair and recovery, similar to how a vaccine prepares the body to fight infection. We believe this could be a therapeutic approach to improve recovery in situations where injuries can be anticipated, such as surgery, combat or sports.”

Could we help senior citizens heal as fast as high school seniors?
Another application for this therapeutic approach may be for the elderly. Lots of things slow down when you get older including your body’s ability to heal itself. This observation sparks an intriguing question for Rando:

“Stem cell activity diminishes with advancing age, and older people heal more slowly and less effectively than younger people. Might it be possible to restore youthful healing by activating this [HGFA] pathway? We’d love to find out.”

I bet a lot of people would love for you to find out, too.

jCyte starts second phase of stem cell clinical trial targeting vision loss

retinitis pigmentosas_1

How retinitis pigmentosa destroys vision

Studies show that Americans fear losing their vision more than any other sense, such as hearing or speech, and almost as much as they fear cancer, Alzheimer’s and HIV/AIDS. That’s not too surprising. Our eyes are our connection to the world around us. Sever that connection, and the world is a very different place.

For people with retinitis pigmentosa (RP), the leading cause of inherited blindness in the world, that connection is slowly destroyed over many years. The disease eats away at the cells in the eye that sense light, so the world of people with RP steadily becomes darker and darker, until the light goes out completely. It often strikes people in their teens, and many are blind by the time they are 40.

There are no treatments. No cures. At least not yet. But now there is a glimmer of hope as a new clinical trial using stem cells – and funded by CIRM – gets underway.

klassenWe have talked about this project before. It’s run by UC Irvine’s Dr. Henry Klassen and his team at jCyte. In the first phase of their clinical trial they tested their treatment on a small group of patients with RP, to try and ensure that their approach was safe. It was. But it was a lot more than that. For people like Rosie Barrero, the treatment seems to have helped restore some of their vision. You can hear Rosie talk about that in our recent video.

Now the same treatment that helped Rosie, is going to be tested in a much larger group of people, as jCyte starts recruiting 70 patients for this new study.

In a news release announcing the start of the Phase 2 trial, Henry Klassen said this was an exciting moment:

“We are encouraged by the therapy’s excellent safety track record in early trials and hope to build on those results. Right now, there are no effective treatments for retinitis pigmentosa. People must find ways to adapt to their vision loss. With CIRM’s support, we hope to change that.”

The treatment involves using retinal progenitor cells, the kind destroyed by the disease. These are injected into the back of the eye where they release factors which the researchers hope will help rescue some of the diseased cells and regenerate some replacement ones.

Paul Bresge, CEO of jCyte, says one of the lovely things about this approach, is its simplicity:

“Because no surgery is required, the therapy can be easily administered. The entire procedure takes minutes.”

Not everyone will get the retinal progenitor cells, at least not to begin with. One group of patients will get an injection of the cells into their worst-sighted eye. The other group will get a sham injection with no cells. This will allow researchers to compare the two groups and determine if any improvements in vision are due to the treatment or a placebo effect.

The good news is that after one year of follow-up, the group that got the sham injection will also be able to get an injection of the real cells, so that if the therapy is effective they too may be able to benefit from it.

Rosie BarreroWhen we talked to Rosie Barrero about the impact the treatment had on her, she said it was like watching the world slowly come into focus after years of not being able to see anything.

“My dream was to see my kids. I always saw them with my heart, but now I can see them with my eyes. Seeing their faces, it’s truly a miracle.”

We are hoping this Phase 2 clinical trial gives others a chance to experience similar miracles.


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