Stem cell stories that caught our eye: herding stem cells, mini autistic brains, tendon repair and hair replacement

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.

Major advance in getting stem cells to behave.  The promise of embryonic stem cells comes from their ability to become any cell type in the body, but medical uses of the cells have been hampered by our poor ability to quickly get them to mature into pure populations of a desired adult tissue. Scientists at Stanford, partially funded by CIRM, and the Genome Institute of Singapore have teamed up to better understand the normal road map of how the various tissues develop in the embryo and in turn fine tune the recipes used to make specific tissues in the lab. They claim to have created pure colonies of 12 different specialized tissues in half the time or less of normal procedures, which usually result in an undesired mix of cells.

 “The problems of making or isolating pure samples of one specific cell type has been a substantial barrier to medical uses of embryonic stem cells. This research looks like a way around that problem,” said Hank Greely, a medical ethicist at Stanford not involved in the work in an article in the East Bay Times.

 

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Weissman

This is a problem researchers around the world have been trying to crack since human embryonic stem cells were first isolated in 2008. The brief paragraph above on how they did it does not do justice to a very elegant and complex research project led by one of the leaders of the field, Irving Weissmann. Stanford’s press release provides more detail about how they achieved the milestone, which should significantly accelerate the field of regenerative medicine.

 

 

Mini brains to figure out oversize brains.  The many forms of autism have many different causes—though most are unknown—and a wide array of symptoms and physical manifestations. An international team has used a lab dish “mini-brain” model to discover the cause of one form of autism, one linked to over-sized brains, which occurs in about 20 percent of children with autism spectrum disorder (ASD).

Autistic neurons Muotri

Nerve precursor cells grown from iPS cells created from children with autism. Inhibitory nerves (in red) are not in sufficient numbers.

A team led by Alysson Muotri at the University of California, San Diego (UCSD), started with tissue samples from children with the disorder and reprogrammed them into iPS type stem cells. They matured those stem cells, first into nerve progenitors and then into the various nerves that in normal cells would result in mini-brains in the lab dish.  But instead of a healthy mix of cells that promote and inhibit nerve growth, they found a lack of inhibitory nerves allowing the overgrowth seen in the condition. They also showed the nerve cells did not send signals to each other properly; they lacked synchronization.

 “The bottom line is that we can now effectively model idiopathic ASD using a cohort of individuals selected by a clear endophenotype. In this case, brain volume,” said Muotri, in a university press release posted by Health Canal. “And early developmental brain enlargement can be explained by underlying molecular and cellular pathway dysregulation, leading to altered neuronal cortical networks.”

More important, they treated the nerves in the dish with a drug, IGF-1, that is currently being tested in the clinic for autism,  and found a reversal of the nerve miss-firing in some of the samples. Their model should make it easier to test more potential drugs, as well.

It has been a big week for improved understanding of ASD. Earlier in the week Fred Gage’s team across the street from UCSD at the Salk institute—where Muotri worked as a post-doctoral fellow—published a causal link for another form of autism, which my colleague Karen Ring wrote about earlier this week in The Stem Cellar.

 

shutterstock_425039020Help for weekend warriors. How many of your friends have ended up on crutches after a weekend of too much basketball or tennis, with a diagnosis of a torn ligament or tendon? And have they said they wished they had broken a bone instead because it would heal faster? Medicine has not been able to speed the healing of those delicate connecting straps in large part because we haven’t known much about how they are created during development. So a team at the Scripps Research Institute set out to find out how they develop and heal naturally.

 “If we understand the molecular mechanisms of tendon development, we can apply the findings to develop a new regenerative therapy for tendon diseases and injuries,” said team leader Hiroshi Asahara in an institution release posted by Sciencecodex.

 They found one gene in particular linked to tendon development and repair in an animal model. They used the new trendy gene editing tool CRISP to regulate the gene in rats. They found the gene results in the production of more tenocytes, which are needed to maintain healthy tendon. That pathway now becomes a target for developing new therapies to help those hobbling friends.

 

For the follicular challenged. On a lighter note, one of the least impactful but most common medical conditions, hair loss, has become a target of therapy development by many university and industry teams. Forbes posted a run down about the activities of some of the leaders of the hair pack.

Not all the author’s science is spot on, for example, when talking about the only organs that constantly regenerate the author ignored the fact that our gut lining turns over about every four days. But he provides a good review of how our hair follicles generally do a good job of replenishing hair and what goes wrong when they fail.

The author focuses most on the work of Japan’s RIKEN Institute, providing an easy to follow info-graphic on how the team there envisions harvesting a small skin sample, sorting the stem cells out of the hair follicles in the sample, growing those stem cells in the lab many fold and then injecting cells back to where they are needed. That team hopes to have a commercial product by 2020. In the meantime, the top of my head will remain intimately acquainted with sun screen.

Stem cell stories that caught our eye: heart repair, a culprit in schizophrenia, 3-parent embryos and funding for young scientists

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.

Chemicals give stem cells heart.  Coaxing stem cells into improving the function of failing hearts has proven quite difficult. Many trials have used a type of stem cell found in fat and bone marrow, called mesenchymal stem cells, to release factors believed to reduce scarring after a heart attack and improve the growth of new blood vessels to nourish the damaged area. But they have produced spotty and only modest positive results. CIRM funds a team at Capricor that uses related cells, but retrieved from heart tissue and believed to release factors that are more efficient in fostering repair—the results are still pending.

Get-Over-Heartbreak-Step-08 This week a Belgian company, using technology developed by the Mayo Clinic in Minnesota, announced positive results for a third option. They start with the stem cells from bone marrow, but in the lab treat them with a cocktail of chemicals that take them part way down the path to becoming heart muscle—into cells called cardiac progenitors. Having shown safety and initial signs of benefit in Phase 1 and 2 trials in Europe, the company Celyad launched the first part of a Phase 3 trial in 2012 and released the results this week.

The company’s research team found that, as with many breakthrough therapies, the most important aspect of early trials is defining which patients are most likely to benefit. The results did not show a benefit for the entire patient group lumped together, but did show significant gain for the 60 percent who fit a certain profile of symptoms at the start of the study. Twin Cities Business wrote about the research that originated in its home state, quoting the lead researcher with OLV Hospital in Belgium, Jozef Bartunek:

 “The results seen for a large clinically relevant number of the patients are groundbreaking,” adding that the results would direct the selection of patients for the second part of the trial to be conducted in the U.S.

The fundamental work done by researchers at Mayo discovered the mechanisms that drive an embryonic stem cell to become heart cells and used that information to develop the cocktail of chemicals that can turn ordinary adult stem cells into cardiac progenitors.

 

Stem cell model fingers culprit in brain. We were all taught the dogma about the path from genes to our tissues: DNA to RNA to protein. And we learned that two types of RNA did the heavy lifting in this transition from genetic recipe to functioning tissue. But RNAs have turned out to be a much more complex family of genetic players, with several types regulating genes rather than coding for any specific function. Some of the most active of these are the micoRNAs with more than 2,000 identified.

A CIRM-funded team at the Salk Institute in La Jolla has fingered one microRNA, miR-19, as playing a role in the faulty wiring seen among nerves in patients with schizophrenia. We always have a few nerve progenitor cells maturing into nerves. But the team found that when they altered the levels of miR-19 the new nerves did not migrate to where they were needed. So, the researchers made iPS type stem cells from patients with schizophrenia, matured them into nerves and looked at miR-19 levels and found them elevated. They also showed the nerve cells did not migrate properly.

 “This is one of the first links between an individual microRNA and a specific process in the brain or a brain disorder,” said senior author Rusty Gage, in an institute press release posted by trueviralnews.

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Over expressing the microRNA miR-19 resulted in new nerves migrating and branching abnormally (right) compared to untreated cells (left)

 

Profile of 3-parent pioneer.  No matter where you stand on the ethics of the “three-parent” fertilization technique that has been much in the news this year, you will enjoy reading Karen Weintraub’s well researched and well written piece about the leading pioneer in the field, Shoukhrat Mitalipov in STAT this morning.

 

Mitalipov-2

Pioneer Mitalipov

The technique focuses on the 37 genes that reside in our cells’ mitochondria rather than in the cells’ nucleus. We only inherit those genes from our moms because we only get the mitochondria in mom’s egg. So, when a woman has a disease-causing mutation in one of those genes, she could have a healthy child that mostly matched her genetic makeup if she could just swap out her mitochondria for someone else’s. That is exactly what the new technique accomplishes.

So far, it has only been tried in monkeys, the oldest of those offspring are now 7 but they are males. The first female is just 4 and since monkeys don’t reproduce until age 6 or 7, and the FDA wants to see how her babies fare, it will be some time before the procedure gets the green light to move forward in humans. None of the 3-parent monkeys show any health issues so far.

Karen’s piece paints a detailed account of the research’s protractors and detractors, as well putting a human face on the man leading the charge. As someone who reads regular posts from a cousin with a child struggling from “Mito” disease, I am rooting for this protagonist.

 

Funding challenge for young stem cell scientists.  A new study in the journal Cell Stem Cell quantifies a lament you hear anytime you are around young researchers, they have a hard time competing with older researchers in the field. The author of the report, Misty Heggeness from the National Institutes of Health, was quoted in news outlets including the San Diego Union Tribune and the blog Science 2.0 on a related issue that should set off alarm bells. If young people are not attracted to the field or fail to stay in the field, at the same time established scientists are nearing retirement age, we could end up with a gap in the research workforce in a few years.

 “From a policy and leadership perspective, one needs to understand what the near future year implications of an aging workforce are. If a system discourages younger cohorts from staying and is heavily composed of older cohorts who will exit the workforce in the near term, who will replace them?”

Part of the problem young researchers have seems to be baked into the current system. Young researchers compete fairly well with older ones on individual applications, but older researchers have the resources to file a lot more applications.  They have more personnel in their labs, freeing them up to write applications, and that personnel also produces the preliminary data that are often needed to even meet application requirements.

The Union Trib piece pointed out that older and younger stem cell scientists are both doing better with funding in California because of CIRM.

Stem cell stories that caught our eye: growing muscle, new blood vessels and pacemakers and Tommy John surgery

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.

Better way to grow muscle.  The specialized stem cells responsible for repairing muscle, the satellite cells, have always been difficult to grow in large quantities in the lab. They have a strong natural hankering to mature into muscle. Researchers have not been able to keep them in their stem cell state in the lab and that prevents creating enough of them for effective therapies for diseases like muscular dystrophy.

new muscle Kodaira

New muscle fibers in green grown in mice from satellite stem cells

A team at the National Institute of Neuroscience in Kodaira, Japan, published what seems to be a simple solution to the problem. In a press release from the publisher of the Journal of Neuromuscular Diseases posted by Science Daily they reported that adding just one protein to satellite cells allowed them to grow indefinitely in the lab and expand to the point they could provide a meaningful transplant that resulted in muscle repair in mice.

 “This research enables us to get one step closer to the optimal culture conditions for muscle stem cells,” said Shin’ichi Takeda from the institute.

The protein they used, leukemia inhibitory factor, and its downstream impacts on other genes is now the subject of their ongoing research.

 

Regenerating heart vessels. A CIRM funded team at Sanford Burnham Prebys Medical Discovery Institute (SBP) in San Diego and at Stanford University have shown that repressing a single gene can encourage the formation of new blood vessels in the heart. Creating those new conduits for oxygen after a heart attack could reduce damage to the heart muscle and prevent development of heart failure.

Building new blood vessels requires coordination of several growth factors and clinical trials evaluating individual factors have resulted in failure. The SBP team found that a single gene repressed all those needed factors and blocking it could let them do their job and create new blood vessels.

Mark Mercola

Mark Mercola

“We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart,” said senior author Mark Mercola, a professor at SBP and at Stanford, in an institute press release. “RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes.”

 The authors also suggested that RBPJ itself might be beneficial in cancer if it can inhibit the new blood vessels tumors need to thrive.

 

Bionic patch as pacemaker.  Chemists at Harvard have designed nanoscale electronic scaffolds that can be seeded with heart cells and are able to conduct current to detect irregular heart rhythms and potentially send out electrical signals to correct them.

 “Rather than simply implanting an engineered patch built on a passive scaffold, our works suggests it will be possible to surgically implant an innervated patch that would now be able to monitor and subtly adjust its performance,” said Charles Lieber the senior author in a university press release posted by Phys.Org. The research was published in Nature Nanotechnology

 With its electronics built into the patch that is integrated into the heart, Lieber suggested the bionic patch could detect heart rhythm problems sooner than traditional pace makers. Another use for the patch he suggested could be to screen potential drugs.

 

Alternate to Tommy John in pictures. Sports fans generally have a vague idea of what Tommy John surgery is. First performed on baseball pitcher Tommy John of the LA Dodgers in 1974, the surgery replaces a torn elbow tendon with one from another part of the body.  A number of baseball players in the past couple years have made headlines because they sought out an alternative to this invasive procedure using stem cells.

The players sometimes improve, but with their high-priced team doctors also demanding extensive physical therapy and other interventions, we don’t really know how much of the improvement is due to the stem cells.  I am not aware of controlled clinical trials looking at the alternative therapy.

LA Angels Andrew HeaneyBut given how much it is in the news, I thought it would be good to share this excellent info-graphic from the LA Times explaining exactly what happens with the stem cell version of the Tommy John procedure. The Times posted the graphic yesterday, and then today, papers around the country ran stories that the most recent famous recipient of the cells, Los Angeles Angels lefthander Andrew Heaney, was going to have the old-fashioned surgery today because the stem cell treatment did not work in this case.

There may be some individuals, likely those with only partial tears who might benefit from this stem cell procedure that uses a type of stem cell that is not likely to replace tendons, but can release factors that summons the body’s natural healing apparatus to do a better job.  But until more formal clinical trials are conducted, it will be hard for     doctors to know who would and would not benefit.

Stem cell stories that caught our eye: hearts with nerve, keeping adult stem cells as stem cells and lab models for the inner ear and pituitary

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.

Hearts with nerve.  When trying to heal a damaged heart you can’t just worry about the heart muscle, you also need to pay attention to the nerves that tell the muscle what to do. A team at John Hopkins has grown nerves from stem cells in the lab that connect to heart cells growing in the same dish, a key step to making the two tissues collaborate where you need them.

Specifically, the team grew sympathetic nerves—a name that never made much sense to me, but basically refers to all those nerves that function without us thinking about their role, like breathing and heartbeat. Faulty sympathetic nerves lead to several diseases including high blood pressure. While it will likely be many years before this work leads to lab-grown heart muscle and nerves teaming up in actual patients, using nerves grown from stem cells made from patients, teams can begin studying those diseases in the lab now.

The researchers published their work in Cell Stem Cell, and ScienceDaily posted the university’s press release. Much of the work involved what has become classic in stem cell research, trying many different combinations of growth factors applied at different moments in time until they arrived at just the right recipe to end up with sympathetic nerves.

 

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Lab grown inner ear structure (Indiana University)

Inner ear grown in a dish.  Researchers at Children’s Hospital, Boston, and Indiana University have succeeded in growing a sac-like tissue that contains the inner ear organs responsible for balance. Starting with mouse embryonic stem cells, the resulting one millimeter structure contained functioning sensory hair cells critical to hearing.

Jeffrey Holt of Children’s said, in the hospital’s Vector blog, that he hopes to use the lab model of the inner ear to test potential therapies for balance disorders he sees in children coming to the facility. The lab-grown tissues seem to behave like the real thing, responding to mechanical stimuli by producing tiny electrical currents. The team published its research in Nature Communications.

 

Getting adult stem cells to stay stem cells.  While pluripotent stem cells like embryonic stem cells can generally be grown in the lab indefinitely, most stem cells from adult tissue eventually mature into specific adult tissue and loose the stem cell property of being able to renew themselves. Researchers at Harvard and Massachusetts General Hospital (MGH) developed a process that keeps adult stem cells from maturing into specific tissue. This could eventually help teams scaling up production of potential therapies but can already speed up and reduce the cost of much of the research getting to that point.

The MGH team worked with airway stem cells, which have been particularly hard to maintain in the lab and require constant collection of new cells that can require invasive procedures such as bronchoscopy. This has made diseases such as asthma and COPD hard to study using stem cell models of disease, which are generally more accurate than animal models.

They started by looking at what internal cellular signaling pathways were active in cells that were maturing into specific tissue but that were not active in the stem cells. They found two such pathways and developed ways to shut down those cell signals. That in turn kept cell in the stem cell state and allowed them to be grown in large quantities in the lab. They were even able to do this with the few airway stem cells that patients cough up when collecting a sputum sample. This would greatly simplify stem cell collection for researchers and patients.

“We also found that the same methodology works for many tissues of the body — from the skin to the esophagus to mammary glands. Many of these organ tissues cannot currently be cultured, so it remains to be seen whether scientists in these areas will be able to grow stem cells from samples acquired from other minimally invasive procedures, including the collection of secretions. If all this becomes possible, it would represent a big step forward for personalized medical approaches to disease,” said Jayaraj Rajagopal, senior author on the paper published in Cell Stem Cell in an MGH press release posted by ScienceDaily

 

Tunable pituitary tissue. While prior research has reported creating tiny pituitary organoids in a dish, those tissues were not very precise in what hormones they produce. Given the fact that the pituitary gland secretes hormones for growth, reproduction and the stress response, and patients with pituitary disease have varying deficiencies in specific hormones, random production of various hormones isn’t likely to be effective treatment.

pituitarytis

Pituitary cells grown from stem cells

Now a team at the Sloan Kettering Institute for Cancer Research led by Lorenz Studer has developed a system of adjusting two factors used to drive stem cells to become pituitary tissue. This system results in adjustable proportions of the tissue that produces different hormones. That way you can get more or less of the various hormones that a patient may need.

When transplanted into rats, the lab grown tissue succeeded in secreting multiple hormones and causing appropriate responses in the animals. Bastian Zimmer, the first author on the paper in Stem Cell Reports, suggested the technique could be used to generate specific cell types for patients with different types of hypopituitarism.

“For the broad application of stem cell-derived pituitary cells in the future, cell replacement therapy may need to be customized to the specific needs of a given patient population,” Zimmer said in a release provided by the journal and posted by MedicalXpress.

Stem cell stories that caught our eye: hopeful stroke data, new target for muscular dystrophy and a rave from Silicon Valley

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.

Stroke study offers hope.  The dogma in stroke recovery says six months after the event patients will have recovered as much as they ever will. A research team at Stanford and the University of Pittsburg may have proven that wrong. They injected mesenchymal stem cells (MSCs) from donor bone marrow directly into the brains of 18 patients and saw significant improvement in the patients’ mobility.

Gary Steinberg, the lead researcher at Stanford where 12 of the patients were treated, offered appropriate caution in a university release stating that more and bigger clinical trials will be needed to verify these results:

“This was just a single trial, and a small one. It was designed primarily to test the procedure’s safety. But patients improved by several standard measures, and their improvement was not only statistically significant, but clinically meaningful. Their ability to move around has recovered visibly. That’s unprecedented.”

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At least one patient was able to abandon her wheel chair

At least one patient was able to abandon here wheel chair.

News outlets around the world ran the story including CNBC and Hufffington Post, which included an interview with Sonia Olea Coontz who had one of the more dramatic recoveries. Like most of the patients, Coontz was more than a year out from her stroke and generally considered unable to regain any lost function, but after the injection her right arm and leg “woke up” in her words.

The team used MSCs from two donors that had been modified to enhance their ability to secrete factors that can foster the innate healing ability of the brain. Steinberg noted that the stem cells did not stay in the brain for much more than a month. But, during that time they seem to have done something pretty amazing. Can’t wait to see if the team repeats this result in a planned 156-patient trial.

 

 Stem cell decisions and muscular dystrophy. While most muscle repair relies on a type of stem cell that can only become muscle, a second type of stem cell that can become muscle or fat also has a role and might provide a way to intervene in the muscle wasting of muscular dystrophy. A team at Rockefeller University in New York City has found a gene that can direct those cells, called pericytes and PICs, to preferentially become muscle.

Previous work had shown that the loss of the protein laminin was associated with some forms of muscular dystrophy and that injecting it directly into the muscle of mice did alleviate some of their muscular dystrophy. But laminin does not migrate from the injection site so in humans would require far too many injections. So the Rockefeller researchers looked to see how laminin affects the activity of genes—whether they are turned on or off—in those special stem cells. They found one gene in particular, gpihbp1, that when forced on could result in the stem cells making much more muscle.

 “Our data suggests that gpihbp1 could be a novel target for the treatment of muscular dystrophy,” said team leader Sidney Strickland in an article posted by Scicasts.

 The researchers published their work in the journal Nature Communications.

 

Silicon Valley leader pushes stem cells. Eric Schmidt, former CEO of Google and current executive chairman of its parent company Alphabet, told The Economic Club of New York this week that America needs to concentrate on transformative big ideas, and he included stem cell science among those.

Google's Eric SchmidtWhen he talked about tackling important problems with science and technology he cited 3D printing of buildings and using stem cells to grow body parts as examples. In an article on uncova.com he said he is seeing an “incredible revolution in medicine and this incredible revolution that’s going on in knowledge.”

When the interviewer, Charlie Rose, asked him whether, if he was starting over today, if he would go into computer science or biology, he answered with an anecdote about a computer scientist who went into biology marrying the two.

 

Stem cell stories that caught our eye: reducing radiation damage, making good cartilage, watching muscle repair and bar coding cells

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.

A bomb blastaStem cells key to reducing radiation damage. With the anniversary of Hiroshima and President Obama’s historic visit to the site all over the news this week, it was nice to read about research that could result in many more people surviving a major radiation event—either from a power plant accident or the unthinkable repeat of history.

Much of the life-threatening damage that occurs early after radiation exposure happens in the gut, so a way to reduce that damage could buy time for other medical care. A team at the University of Texas Medical Branch at Galveston has discovered a drug that activates stem cells in the gut, which help maintain a healthy population of crypt cells that can repair gut damage.

A single injection of the small protein drug in mice significantly increased their survival, even if it was given 24 hours after exposure to radiation. The researchers published their work in the journal Laboratory Investigation and in a story written for MedicalNewsToday the lead author, Carla Kantara suggested the role the drug might have:

 “The current results suggest that the peptide may be an effective emergency nuclear countermeasure that could be delivered within 24 hours after exposure to increase survival and delay mortality, giving victims time to reach facilities for advanced medical treatment.”

The small protein, or peptide, named TP508, has already been tested in humans for diabetic foot ulcers so could be tested in humans fairly quickly.

 

Making good cartilage for your knees. Rarely a week goes by that I don’t tell a desperate osteoarthritis patient with painful knees that I am treating my own rotten knees with physical therapy until we learn how to use stem cells to make the right kind of cartilage needed for lasting knee repair. So, I was thrilled to read this week that the National Institutes of Health awarded Case Western Reserve University in Cleveland $6.7 million to develop a center to create standardized systems for monitoring stem cells as they convert into cartilage and for evaluating the resulting cartilage.

ear_wakeforest There are a couple problems with existing attempts to use stem cells for knee and other cartilage repair. First not all cartilage is equal and too often stem cells form the soft kind like in your earlobe, not the hard kind needed to protect knees. Also, it has been hard to generate enough cells to replace the entire area that tends to be eroded away in osteoarthritis, one of the leading causes of disability.

The new center, which will be available to researchers anywhere in the world, will develop tools for them to measure four things:

  • which genes are turned on or off as stem cells take the many steps toward becoming various forms of cartilage;
  • predict the best makeup of the extracellular matrix, the support structures outside cells that help them organize as they become a specific tissue;
  • evaluate the biochemical environment around the cells that helps direct their growth;
  • measure the mechanical properties of the resulting cartilage—is it more like the ear or the knee.

NewsWise posted the university’s press release

 

Damaged muscle grabs stem cells.  All our tissues have varying skills in self repair. Muscles generally get pretty high marks in that department, but we don’t really know how they do it. A team at Australia’s Monash University used the transparent Zebra fish and fancy microscopes to actually watch the process.

When they injured mature muscle cells they saw those cells send out projections that actually grabbed nearby muscle stem cells, which regenerated the damaged muscle. They published their findings in Science, the university issued a press release and a news site for Western Australia, WAtoday wrote a story quoting the lead researcher Peter Currie:

 “A significant finding is that the wound site itself plays a pivotal role in coordinating the repair of damaged tissue. If that response could be sped up, we are going to get better, or more timely, regeneration and healing.”

The online publication posted four beautiful florescent images of the cells in action.

 

muscle stem cells Monash

Muscle stem cells in action

“Bar coding” cells points to better transplants.  A team at the University of Southern California, partially funded by CIRM, developed a way genetically “bar code” stem cells so they can be tracked after transplant. In this case they watched the behavior of blood-forming stem cells and found the dose of cells transplanted had a significant impact on what the cells became as they matured.

The general dogma has blood stem cells producing all the various types of cells in our blood system including all the immune cells needed by cancer patients after certain therapies. But the USC tracking showed that only 20 to 30 percent of the stem cells displayed this do-it-all behavior. The type of immune cells created by the remaining 70 to 80 percent varied depending on whether there was a low dose of cells or a high dose, which can be critical to the effectiveness of the transplant.

 “The dose of transplanted bone marrow has strong and lasting effects on how HSCs specialize and coordinate their behavior,” said Rong Lu, senior author, in a USC press release posted by ScienceDaily. “This suggests that altering transplantation dose could be a tool for improving outcomes for patients — promoting bone marrow engraftment, reducing the risk of infection and ultimately saving lives.”

Stem cell stories that caught our eye: Zika virus and brain stem cells, new guidelines, re-growing tails and better iPS cells

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.

Three more studies on Zika and brain stem cells. It’s heartening to see how quickly the scientific community has reacted to the recent Zika virus epidemic. They have already completed and published dozens of research projects. And science journals have responded by not only speeding up their often slow process to get results published, but also some are removing pay walls to ease disseminating the data.

After a pair of studies earlier this month showed how the virus could impact brain stem cells in mini human brain “organoids” in the lab, three studies this week showed how the virus does its damage in animal models. A colleague wrote two blog posts on the human mini-brain studies, one revealing the entry point the virus uses to enter brain stem cells and the other finding the virus negatively impacts the ability of brain stem cells to specialize into mature brain.

 

Zika in placenta Wash U

Zika virus (red) in a mouse placenta (Washington U.)

While those organoids can tell us a lot, they don’t show what happened when the fetus matures, so the new mouse models provided the first conclusive link between infection and microcephaly—the small brains seen in children born following their mother’s infection with the virus. But the three studies muddied the water a bit on the cause of the reduced brain size. One suggested that damage to the placenta could have reduced blood flow to the developing fetus. The other studies showed that the virus does indeed infect brain stem cells, but one suggested that the bulk of the damage from the virus occurs later in pregnancy acting directly on mature nerve cells, not the stem cells.

The papers in Cell from Washington University in St. Louis, in Nature, from the University of California, San Diego and in Cell Stem Cell from the Chinese Academy of Science got wide media coverage. Genetic Engineering News and Science Magazine did some of the most thorough reporting and Newsweek wrote a piece a bit easier to understand.

 

Stem cell research guidelines.  When an august scientific body issues guidelines for its work, the public generally either ignores it or never hears about it. That paradigm shifted a bit this week when the International Society for Stem Cell Research issued revised guidelines for numerous aspects of regenerative medicine research and practice. A large part of the difference probably resulted from the group self-cautioning its members to avoid hype and not oversell their results.

The Bloomberg business wire issued a story with the headline, “Stop Hyping Stem Cell Science, Say Stem Cell Scientists.” Four scientific journals simultaneously published various reviews of the guidelines including one in Science authored by five members of the 25-person committee that drafted them. That piece carried the title, “Confronting Stem Cell Hype.”

One of the authors, Tim Caulfield of the University of Alberta, acknowledged changing the discourse in the field will not be easy:

 “Because the forces that twist how science is communicated are complex, systemic, and interrelated, correcting for science hype will not be easy.”

Beyond the hype, the guidelines address several important issues in our field calling for:

  • a process to review all embryo research, not just when the embryo is destined to be a source of stem cells;
  • support for laboratory research on genetically modifying sperm, eggs and embryos, but banning such techniques for clinical use at this time;
  • defining proper research and clinical use of techniques to swap out healthy mitochondria, for defective ones in cells;
  • allowing compensation for women who donate eggs for research within certain defined parameters
  • creating robust standards for evaluating the outcome of stem cell clinical trials.

 

Just a few switches to regrow a tail.  Many lizards and amphibians regrow their tails with ease, but prior research has shown a great many genes get turned on to make it happen. Now, a team at Arizona State University has shown that just three genetic switches orchestrate much of that gene activity.

arizona_green anole lizard

Green Anole lizard (Arizona State U.)

The tiny genetic components called microRNAs turn out to be very powerful on-off switches for genes and can control many different genes at the same time.

 “Since microRNAs are able to control a large number of genes at the same time, like an orchestra conductor leading the musicians, we hypothesized that they had to play a role in regeneration,” said senior author Kenro Kusumi in a story in Bioscience Technology.

 The group hopes their research will lead to ways to get tissue regeneration in humans for repairing damage such as spinal cord injury or worn knee cartilage.

 

Making better iPS cells.  Although we have known for a decade the basics of how to turn an adult cell into an embryonic-like stem cell, iPS cells, virtually that entire time researchers have sought ways to make them even more like embryonic stem cells. Too often iPS cells retain memory of the adult cell they came from and stubbornly refuse to turn into certain other types of tissue.

Researchers at the University of Pennsylvania have shed light on this stubborness using an emerging field called “3D epigenetics.”  Epigenetics looks at the various controls that turn genes on and off, but it traditionally cannot take into account the effect of DNA folding that puts genes next to each other adding a layer of regulation based on juxtaposition.  They found that in some iPS cells the DNA folding looked more like mature cells than embryonic stem cells, but that by manipulating the way the cells were grown they could modify that folding.

 “Our observations are important because they suggest that, if we can push the 3-D genome conformation of cells that we are turning into iPS cells to be closer to that of embryonic stem cells, then we can possibly generate iPS cells that match gold-standard pluripotent stem cells more rapidly and efficiently,” said graduate student Jonathan Beagan in a university press release.

Stem cell stories that caught our eye: two-week old embryos in the lab, gene edited disease model, recipe for bone and cancer milestone

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.

Two-week embryos grabbed headlines. I have rarely seen as many online news outlets pick up a basic science story as happened this week with the news that an international team had nearly doubled the time it is possible to keep an embryo alive in a lab dish. While the research has tremendous potential to improve the chances couples can bring a new life into their families, the bulk of the coverage focused on the ethical issues surrounding the research embryo itself.

 

Imaris Snapshot

Molecular markers highlight various parts of a 12-day old embryo

After countless national and international confabs in the late 1970s and into the 1980s, research organizations around the world adopted the policy that no one would grow an embryo in the lab beyond 14 days. That is the point the “primitive streak” develops marking the first time cells within the embryo adopt individual identities. But the rule required no enforcement because no one knew how to coax an embryo into growing beyond nine days, and few could get them even to grow seven.

That changed this week, when the team led by Ali Brivanlou at Rockefeller University got embryos to grow to 13 days. They followed a procedure developed by a team colleague in Cambridge, UK, in mice reported earlier. They basically made the embryos feel more at home. They tested many different chemicals to add to the lab dish to optimize growth and gave the embryos a rigid structure more like a uterine wall.

They successfully mimicked implantation, the key step when the few-day-old embryo attaches to the uterus. Failure in this critical step is a key cause of infertility, but we have never been able to find out how it happens, and what little we do know suggests the mouse model for that step is not a good one for looking at human fertility.

 “This portion of human development was a complete black box,” said Brivanlou in a university press release picked up by many outlets including Bioscience Technology. She later added: “With this work, we can really appreciate the differences between human and mouse, and across all mammals. Because of the variations between species, what we learn in model systems is not necessarily relevant to our own development, and these results provide crucial information we couldn’t learn elsewhere.”

Because of that incredible potential value in this work, the journal Nature that published the research paper also ran a commentary about the current 14-day limit on growing embryos in the lab. It does not call for changing the policy at this time, but it does suggest the conversation–likely to be long–about whether the benefits of this work outweigh the ethical trip wires should begin soon.

The Washington Post wrote one of the most balanced pieces discussing both sides of the issue.

 

A mightier disease-in-a-dish model.  We frequently write about using iPS type stem cells to model diseases. Usually this involves getting a skin sample from a patient with a genetically-linked disease, converting it to stem cells and then growing the nerve or other tissue impacted by the disease. But you can also mimic the disease by genetically modifying normal stem cells to have specific mutations. This allows you to start to sorting out the role of individual genes in diseases linked to multiple genes.

 

Neurons from stem cells_TessierLavigne_neurons

Nerves grown from stem cells

One problem with the latter had been that gene editing techniques, particularly the wildly popular CRISPR-Cas9 method, usually edit both strands of DNA, but many disease mutations can do their damage with only a single incorrect gene, so-called heterozygous mutations. Now, another Rockefeller University team, this one led by the University’s president Marc Tessier-Lavigne, developed a way to make the CRISPR edit much more specific and only impact one strand of DNA.

HealthCanal picked up the university’s press release about the work published in Nature. The specific gene editing in this reports involved mutations linked to Alzheimer’s disease.

 

bone-scaffold Hopkins

Printed jaw

A better recipe for bone. Researchers trying to grow new tissue are finding the make-up of the scaffold you use can be more important than the stem cells you put on the structure. A Johns Hopkins team recently reported an improved recipe for making a scaffold for growing bone. Their formula: 30 percent pulverized natural bone and the remainder a special plastic with the mixture extruded using a 3D printer.

 “Bone powder contains structural proteins native to the body plus pro-bone growth factors that help immature stem cells mature into bone cells,” said Hopkins’ Warren Grayson. “It also adds roughness to the PCL (plastic), which helps the cells grip and reinforces the message of the growth factors.”

MDTmag posted the university press release about the research published in ACS Biomaterials Science & Engineering.

 

Licensing moved cancer therapy forward.  We at CIRM are always thrilled when one of our projects hurdles a milestone toward becoming a widely available therapy. One such critical move was announced last month and picked up this week by HealthCanal.

 Oncternal Therapeutics licensed the antibody drug named for our agency, Cirmtuzumab, for further testing of its ability to fight leukemia, and potentially other cancers. The antibody selectively targets a protein on cancer stem cells, ROR1, which has the unwieldy full name “receptor-tyrosine kinase-like orphan receptor 1.” The license also includes rights to other drugs that might be developed targeting ROR1.

University of California, San Diego, which developed Cirmtuzumab, has begun a clinical trial but has not got to a point where it can report results. We covered it in more detail in our series CIRM Fights Cancer.

Stem cell stories that caught our eye: Trifecta of nerve news on aging, Parkinson’s and myelin diseases, also expanding cord blood

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.

rapamycin-effect-on-MILS-neurons

Untreated (top) and treated nerves

To save nerves, make them slow down. Nerves, like all cells, constantly make protein, but that task uses up a lot of energy and older nerves have a limited energy supply. A CIRM-funded team at the Salk Institute has shown that an approved drug can slow down protein production in nerves, conserve energy and help them survive.

The Salk team led by Tony Hunter saw the tamping down effect in a disease-in-a-dish model of Leigh syndrome, an inherited neurodegenerative condition caused by a mutation in mitochondria, the cell’s power plant. They created iPS type stem cells by reprogramming skin cells from a Leigh syndrome patient, grew them into nerves and saw evidence of energy depletion that was reversed when they treated the cells with the drug rapamycin.

 “Reducing protein production in ageing neurons allows more energy for the cell to put toward folding proteins correctly and handling stress,” said team member Xinde Zheng, in a Salk release posted by Scicasts. “The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration.”

Next step for the team will be seeing if their finding holds true in an animal model of the syndrome. They published their findings in eLife.

 

For dopamine nerves turn them on and off.  Many researchers strive to turn stem cells into dopamine producing nerves to replace the chemical signal that is in short supply in Parkinson’s disease patients. But what if they succeed, put the new nerves in patients and they produce too much dopamine? A team, at the University of Wisconsin has a solution, make the new nerves responsive to a drug that can act as an on-and-off switch.

The team grew nerves from stem cells made from iPS type stem cells and genetically engineered them so that they would only produce dopamine in the presence of a certain drug. Brad Fikes at the San Diego Union Tribune wrote a brief story about the research that the team published in Cell Stem Cell.

 He put the news into perspective by noting that early trials implanting dopamine nerves from fetal tissue resulted in some patients having side effects from over production of the nerve signal transmitter.

 

And restoring nerves protective myelin.  Neurons form the basis of all brain function, but they take a family of support cells and tissues to do a good job of directing our muscles, recording memory, etc.  First nerves need the protective insulation called myelin to properly transmit signals. Cells called oligodendrocytes produce the myelin, but they need signals from cells called astrocytes to do their job well. Researchers have known for some time that immature astrocytes do a great job of fostering oligodendrocytes, but mature astrocytes do not, but they have not known why.

Now, CIRM-funded researchers at the University of California, Davis, have isolated a protein secreted by immature astrocytes called TIMP-1 that promotes proliferation of the needed oligodendrocytes, and down the line, the myelin needed to protect neurons.

In the study published in Cell Reports, the researchers created iPS type stem cells and directed them to become astrocytes, stopping the growth at an immature state and implanted them in mice. But before the transplants, they shut down the production of TIMP-1 in some of the astrocytes, and in those mice they saw no increase in the production of myelin.

 

Deng-headshot

Wenbin Deng of UC Davis

The research project leader, Wenbin Deng, speculated in a Davis press release on how the research could eventually help patients with any number of diseases involving myelin loss:

 “We are hopeful that his could lead to a promising therapy for premature brain injury, cerebral palsy, multiple sclerosis, spinal cord injury, white matter stroke and many neurodegenerative diseases.”

 

Key protein for developing blood stem cells.  The stem cells found in umbilical cord have saved thousands of cancer patients by rebuilding their immune system after chemotherapy. But cord blood samples often have too few stem cells to be effective and while a couple teams have reported some progress in expanding the number of stem cells in any one cord sample, more progress is needed.

Researchers at McMaster University reported in the journal Nature this week that they had isolated a protein that controls the development of blood stem cells. That protein, Musashi-2, does not regulate genetic activity at the DNA level, but rather at the next step in the gene-to-protein pathway, regulating the activity of RNA.

In an article posted on the Bioscience Technology website, the team leader Kristin Hope speculated on the value to patients when they learn how to turn this knowledge into making cells for therapy:

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn reducing overall health care costs and wait times for newly diagnosed patients seeking treatment.”

 

Stem cell stories that caught our eye: fashionable stem cells, eliminating HIV, cellular Trojan horse fights cancer

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.

Stem cell fashion for a cause. Science and art are not mutually exclusive subjects. I know plenty of scientists who are talented painters or designers. But you don’t often see science being displayed in an artistic way or art being used to help explain complex scientific topics. I think that in the future, this will change as both subjects have a lot to offer one another.

Stem cell ties are in fashion!

Stem cell ties are in fashion!

Take this story from the University of Michigan for instance. Designer Dominic Pangborn has joined forces with the Heinz C. Prechter Bipolar Research Fund at the University of Michigan (UOM) to design fashionable scarves and ties featuring beautiful pictures of stem cells. The goal of the Prechter Fund scarf and tie project is to raise awareness for mental health research.

The scarves and ties feature pictures of brain stem cells taken by UOM scientists who are studying them to understand the mechanisms behind bipolar disorder. These stem cells were generated from induced pluripotent stem cells or iPS cells that were derived from donated skin biopsies of patients with bipolar disease. Studying these diseased brain cells in a dish revealed that the nerve cells from bipolar patients were misbehaving, sending out electrical signals more frequently compared to healthy nerve cells.

Dr. Melvin McInnis, the Prechter Fund research director, explained:

“By understanding the causes of bipolar disorder, we will be able to develop new treatments for the illness and most importantly, we’ll be able to prevent destructive mood episodes. Our ultimate goal is to allow people to live happy, normal lives.”

Pangborn is passionate about using art to reflect an important cause.

“I decided to add butterflies to the design because they signify metamorphosis. Our society is finally at a point where mental illness is openly talked about and research is taking a turn for the better.”

He plans to release his collection in time for National Mental Health Awareness month in May. All proceeds will go to the Prechter bipolar research projects at UOM.

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

New stem cell therapy could eliminate HIV for good

The stem cells therapies being developed to cure HIV are looking more promising every day. A few are already being tested in clinical trials, and CIRM is funding two of them (you can read more about them here). News came out this week about a new trial conducted at the City of Hope’s CIRM Alpha Stem Cell Clinic. They reported in a news release that they’ve treated their first patient. His name is Aaron Kim, and he’s had HIV since he was born. In 1983, he and his twin sister were born prematurely and due to a complication, Aaron had to get a blood transfusion that unfortunately gave him HIV.

Aaron Kim with nurse. (City of Hope)

Aaron Kim with nurse. (City of Hope)

Aaron thought he would live with this disease the rest of his life, but now he has a chance at being cured. In March, Aaron received a transplant of his own bone marrow stem cells that were genetically engineered to have a modified version of the CCR5 gene that makes his cells resistant to HIV infection. CCR5 is a is a protein receptor on the surface of blood cells that acts as a gateway for HIV entry. The hope is that his reengineered stem cells will populate his immune system with HIV-resistant cells that can eliminate the virus completely.

Dr. John Zaia who is the director the the City of Hope Alpha Clinic explained,

“The stem cell therapy Aaron received is one of more than 20 cure strategies for HIV. It may not cure him, but our goal is to reduce or even halt Aaron’s reliance on HIV drugs, potentially eliminating the virus completely.”

My favorite part of this story was that it acknowledged how importance it is for patients to participate in clinical trials testing promising new stem cell therapies where the outcomes aren’t always known. Brave patients such as Aaron make it possible for scientists to make progress and develop better and safer treatments for patients in the future.

Dr. Zaia commented, “It’s a wonderful and generous humanitarian gesture on Aaron’s part to participate in this trial.”

Stem cell Trojan horse fights cancer

Chemotherapy is great at killing cancer cells, but unfortunately, it’s also great at killing healthy cells too. To combat this issue, scientists are developing new delivery methods that can bring high doses of chemotherapy drugs to the cancer tumors and minimize exposure of healthy tissues.

Mesenchymal stem cells loaded with drug-containing microparticles. Credit: Jeff Karp and Oren Levy, Brigham and Women's Hospital

Mesenchymal stem cells loaded with drug-containing microparticles.
Credit: Jeff Karp and Oren Levy, Brigham and Women’s Hospital

A study published this week in Biomaterials, describes a new drug delivery method that has the potential to be an effective treatment for prostate cancer. Researchers from the Brigham and Women’s Hospital and Johns Hopkins University developed a drug delivery platform using mesenchymal stem cells. They packaged a non-active, prodrug version of a potent prostate cancer chemotherapy drug into microparticles that they loaded into MSCs. When the MSCs and prostate cancer cells were cultured together in a dish, the MSCs released their prodrug cargo, which was then internalized by the prostate cancer cells. The prodrug was then metabolized into its active, cancer-killing form and was very effective at killing the cancer cells.

In a news release picked up by Science Daily, one of the lead scientists on the study, Dr. Oren Levy, further explained the stem cell Trojan horse concept:

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors. Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

If all goes well, the teams plan to develop different versions of their stem cell-based drug delivery method that target different cancers and other diseases.