Stem cell stories that caught our eye: affairs of the heart, better imaging of cells and pituitary glands in a dish

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.

Matters of the heart not simple. The dozens of clinical trials using various types of stem cells to repair hearts after a heart attack have produced some encouraging and some discouraging results. Trials using a type of cell called a c-kit positive progenitor cells have generally produced the more positive changes in patients. But no one is completely sure why.

Get-Over-Heartbreak-Step-08The Scientist used a recent publication in Circulation Research to review the various beliefs about what these heart-derived cells do. The recent paper by University of Louisville’s Roberto Bolli confirmed what several other studies had found: the cells do not create new heart muscle themselves but do release various proteins that seem to direct natural healing. These signals, called paracrine effects, seem to last for many months even if the transplanted cells themselves don’t stick around.

The article quotes a member of a CIRM funded team using c-kit+ cells in a phase 2 clinical trial that published a paper on the paracrine effect a couple years ago:

“They’re just confirming a paradigm we and others established years ago,” said Eduardo Marban, of Cedars-Sinai hospital in Los Angeles.

The author of The Scientist piece also brings in one of the more controversial characters in the field, Piero Anversa, who while at Harvard produced a paper that suggested the c-kit+ cells could produce heart muscle, but that paper was later retracted and led Anversa to move to Switzerland from where he told the writer not all c-kit+ cells are the same. He still maintains some of the cells can produce heart muscle. This is one intrigue of the heart to be continued.

 

Hearts respond to ultrasound.  One theory on what the factors released by implanted stem cells do suggests they enlist the few cardiac stem cells we all have in our hearts. Those cells naturally try to repair the damage after a heart attack, but there just are not enough of them to be very effective. So, the paracrine factors released by donor stem cells may prod them to do a better job. Now a team in Spain suggests ultrasound treatment may do the same thing.

The researchers at the Universidad Politecnica de Madrid applied low-intensity pulsed ultrasound in mice with damaged hearts and found improved performance of the heart stem cells. Laboratory tests suggested the ultrasound treatment improved the cells mobility, in effect made them better able move to the site of damage. MedicalNews.net picked up a piece from the university on the research.

 

Give those cells a hug.  Most of you have seen the many colorful images we post of stem cells with various parts of the cells glowing in different colors. These fluorescent tags on specific proteins in the cells help scientists identify and track cellular bits of interest. They sometimes introduce the tags genetically during development of the cells, but if they want to introduce them into living tissue after the fact, they have trouble getting the often large fluorescent tags into cells in a way that maintains a living cell’s normal function.

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Proteins labeled using the new technique that compresses the cells to create pores

Now teams working at MIT and Goethe University in Frankfurt have refined a technique that squeezes living cells and creates temporary pores that lets the tags into the cells. The teams published their work in Nature Communications and a press release from MIT picked up by Phys.Org offered a quote from one of the authors, Armon Sharei, on the value of the work to the field in general:

“Basically everything that happens in your cells is mediated by proteins. You can start to learn a lot about the basic biology of how a cell works, how it divides, and what makes the cancer cell a cancer cell, as far as what mechanisms go awry and what proteins are responsible for that.”

Another mini-organ, the pituitary.  The list of miniature organs created in the lab has grown to at least a dozen with the creation of pituitary glands by a team at Japan’s RIKEN Center, where some of the other “organoids” have been made. Because the pituitary is tiny, the lab grown version comes closer to the size of the natural one, and may be ready for clinical consideration sooner.

The pituitary gland secretes several hormones that control bodily functions, and when it is out of whack, you really know it. So a replacement would be a boon for patients, who now receive hormone replacement therapy that is not fully effective.

SciCasts wrote a story on the research that provides a nice narrative of the various steps the researchers took to get to a functional mini-organ that worked to correct hormone level when implanted in mice. It ends with a quote from Takashi Tsuji the head of the appropriately named Laboratory for Organ Regeneration:

“This is an exciting step forward toward our ultimate goal, which is to be able to regrow fully functioning organs in the laboratory. We will continue to push ahead with experiments to grow other parts of the body.”

Stem cell stories that caught our eye: watching tumors grow, faster creation of stem cells, reducing spinal cord damage, mini organs

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.

Video shows tumors growing. A team at the University of Iowa used video to capture breast cancer cells recruiting normal cells to the dark side where they help tumors grow.

Led by David Soll, the team reports that cancer cells secrete a cable that can reach out and actively grab other cells. Once the cable reaches another cell, it pulls it in forming a larger tumor.

 “There’s nothing but tumorigenic cells in the bridge (between cells),” Soll said in a story in SciCasts, “and that’s the discovery. The tumorigenic cells know what they’re doing. They make tumors.”

They published their work in the American Journal of Cancer Research, and in a press release they suggested the results could provide an alternative to the theory that cancer stem cells are the engine of tumor growth.  I would guess that before too long, someone will find a way to merge the two theories into one, more cohesive story of how cancer grows.

 

3-D home creates stem cells quicker. Using a 3-D gel to grow the cells, a Swiss team reprogrammed skin cells into iPS-type stem cells in half the time that it takes in a flat petri dish. Since these induced Pluripotent Stem cells have tremendous value now in research and potentially in the future treating of patients, this major improvement in a process that has been notoriously slow and inefficient is great news.

The senior researcher Matthias Lutoff from Polytechnique Federale explained that the 3-D environment gave the cells a home closer to the environment where they would grow in someone’s body. In an article in Healthline, he described the common method used today:

 “What we currently have available is this two dimensional plastic surface that many, many stem cells really don’t like at all.”

At CIRM our goal is to get this research done as quickly as possible and to find ways to scale up any therapy so that it becomes practical to make it available to all patients who need it. Healthline quoted our CIRM scientist colleague Kevin Whittlesey on how the work would be a boon for stem cells scientists with its ability to shave months off the process of creating iPS cells.

 

Help for recent spinal cord injury.  A team at Case Western Reserve University in Cleveland used the offspring of stem cells that they are calling multi-potent adult progenitor cells (MAPCs) to modulate the immune response after spinal cord injury. They wanted to preserve some of the role of the immune system in clearing debris after an injury but prevent any overly rambunctious activity that would result in additional damage to healthy tissue and scarring.

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They published their work in Scientific Reports and at the web portal MD the senior researcher Jerry Silver described the project as targeting a specific immune cell, the macrophage, in the early days following stroke in mice:

 

 “These were kinder, gentler macrophages. They do the job, but they pick and choose what they consume. The end result is spared tissue.”

The team injected the MAPCs into the mice one day after injury. Those cells were observed to go mostly to the spleen, which is know to be a reservoir for macrophages, and from their the MAPCs seemed to modulate the immune response.

 “There was this remarkable neuroprotection with the friendlier macrophages,” Silver explained. “The spinal cord was just bigger, healthier, with much less tissue damage.”

 

Rundown on all the mini-organs.  Regular readers of The Stem Cellar know researchers have made tremendous strides toward growing replacement organs from stem cells. You also know that with a few exceptions, like bladders and the esophagus, these are not ready for transplant into people.

Live Science web site does a fun rundown of progress with 11 different organs. They hit the more advanced esophagus and cover the early work on the reproductive tract, with items on fallopian tubes, vaginas and the penis. But most of the piece covers the early stage research that results in mini-organs, or as some have dubbed them, organoids. The author includes brain, heart, kidney, lung, stomach and liver. They also throw it the recent full ear grown on a scaffold.

Each short item comes with a photograph, mostly beautiful fluorescent microscopic images of cells forming the complex structures that become rudimentary organs.

3D printed human ear.

3D printed human ear.

Mini-stomachs.

Mini-stomachs.

This past summer we wrote about an article on work at the University of Wisconsin on the many hurdles that have to be leapt to get actual replacement organs. Progress is happening faster that most of us expected, but we still have a quite a way to go.

Stem cell stories that caught our eye: colon cancer relapse and using age, electricity and a “mattress” to grow better hearts

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 cells yield markers for relapse in colon cancer. Some colon cancer patients do fine after surgery without any chemotherapy, but it has been hard to predict which ones. A CIRM-funded team at the University of California, San Diego, with collaborators at Stanford and Columbia Universities, found a predictor for the need for chemotherapy by looking at the patients’ cancer stem cells.

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Patients whose colon cancer stem cells tested positive for CDX2 (brown) had a better prognosis.

Previously researchers have looked for markers in the tumors themselves for differences between those who require chemotherapy and those who don’t. Those efforts generally come up empty handed. The current team instead looked for differences in the patient’s cancer stem cells. They found that patients whose stem cells lacked one protein marker called CDX2 did poorer with surgery alone and were candidates for follow-up chemotherapy.

The team published its work in this week’s New England Journal of Medicine and it got wide pickup by online news outlets, but that coverage varied somewhat depending on which group the reporters called. Medical News Today provides the Columbia angle. Newswise distributed a press release with the San Diego voice and BlackDoctor.org used quotes from Stanford as well as the American Cancer Society. The latter lets Stanford’s Michael Clark remind readers that this was a retrospective look back at prior cancer patients and the conclusions need confirmatory studies.

 “The data is extremely strong, but you need a prospective analysis to be 100 percent sure. It should be validated in a prospective trial.”

 

Three studies aim for better heart cells. While researchers have been turning stem cells into heart muscle in lab dishes for several years, getting them to function like normal heart cells either in the dish or when transplanted into animals has been tough. Three research groups published studies this week showing different approaches to making better heart muscle.

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Normal heart muscle cells, courtesy Kyoto University

Age matters

 Biologists at Japan’s Kyoto University found a sweet spot in the age of new muscle cells when they were most likely to engraft and survive when transplanted in animals. They first created reprogrammed iPS-type stem cells and then matured them toward becoming heart muscle for four, eight, 20 and 30 days. The 20-day cells proved the most able to engraft in the mouse hearts and improve their function as seen by echocardiography.

The Kyoto team published its results in Scientific Reports and BiotechDaily wrote an article on the work.

Give them a jolt. 

A group of physician engineers at Columbia University found that exposing lab grown heart muscle cells to electrical stimulation that mimicked the signals the cells would receive in a fetus resulted in stronger, more synchronized heart muscle. They started by engineering the heart muscle cells to grow in three dimensions and then added the electrical signals.

 “We applied electrical stimulation to mature these cells, regulate their contractile function, and improve their ability to connect with each other. In fact, we trained the cell to adopt the beating pattern of the heart, improved the organization of important cardiac proteins, and helped the cells to become more adult-like,” said Gordana Vunjak-Novakovic, the lead author on the paper published in Nature Communications.

 NewsMedical picked up the university’s press release.

Give them a mattress. 

 A team at Vanderbilt University in Tennessee found that growing the heart muscle cells on a commonly used lab gel called Matrigel resulted in cells with a shape and contractile function that matched normal heart tissue. The Matrigel formed a cushiony substrate that one team member referred to as a “mattress” for the cells to grow on that is more like the living environment in an animal than the usual lab dish.

ScienceDaily ran the university’s press release about the study published in Circulation Research. In the release, the team speculated that the matrigel worked through a combination of the flexibility of the gel and unknown growth factors released by the gel itself.

With heart disease still a leading cause of death, learning how to make better repair tissue could lead to major improvements in quality and length of lives. Of the 600-plus stem cell clinical trails currently active around the world, at least 70 target heart disease, but very few are striving to provide new tissue to repair damaged heart muscle. Generally, they are using stem cells that secrete various factors that help the heart heal itself. CIRM funds one of those trials being conducted by Capricor.

Stem cell stories that caught our eye: Both parents’ diets impact health of offspring, also lab grown fallopian tubes and testicles

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 special post on stem cells and reproductive health

 Mom needs to balance her Omegas. To produce a healthy baby with a robust brain you need young vigorous nerve stem cells. But when mothers-to-be eat a diet with too much of one omega fat and not enough of another, the nerve stem cells in the fetus age too quickly, and produce offspring with smaller brains and abnormal behavior—at least in a mouse study.

salmonA similar diet can occur in human populations where more oils come from nuts and other seeds that have mostly Omega 6 fats rather than fish that have oils with Omega 3 fats. Researchers at Japan’s Tohoku University published the study on the impact of a diet with an omega fat imbalance in the journal Stem Cells and the university posted a press release on EurekAlert.

 

Dad’s diet can impact offspring, too.  Several groups published studies recently showing a man’s diet can impact his fertility and the health of any offspring. One of those studies linked a low protein diet to changes in genes responsible for the healthy development of stem cells in the fetus.

That mouse study was published this week in Science along with a second study on male mice that consumed a high fat diet and produced offspring with a reduced ability to process sugars. A story on Yahoo News briefly describes the two studies along with a couple others on father’s diets from the past two years.

 

Lab-grown fallopian tubes—or bits of them. A woman’s fallopian tubes, those tiny shafts that transport eggs from the ovary to the uterus, present a major challenge to researchers trying to improve fertility. The cause of infertility for many couples may reside in those tiny tubes but they are almost impossible to study in the developing fetus or adults.

fallopian tubesA German research team made major strides in overcoming this barrier by growing bits of the inner portion of fallopian tubes in the lab. They used cells from the lining of donor fallopian tubes that have stem cell-like qualities and grew them in conditions that mimicked the environment of that portion of the growing embryo. Like many other teams who have grown mini organs, or organoids, they found that if you choose the right cells they have an incredible ability to self-form multilayered complex tissues. In this case the epithelial cells they used formed hollow spheres that have the characteristics of natural fallopian tubes.

 “That happened without any additional instruction whatsoever,” one of the researchers, Mirjana Kessler, told Science alert. “The entire blueprint of the fallopian tube must therefore be stored in the epithelial cells.”

The work is far from being able to offer a woman with damaged fallopian tubes a new chance for fertility. But it does offer researchers a great new tool for studying how the tiny organs form and potentially how to repair them.

 

And for the men, potential lab grown testicles. The Wake Forest team led by Anthony Atala that has pioneered growing simple organs such as urinary tract bladders from stem cells, has now grown tiny human testicles in the lab. However, none of their miniature organs grown so far could never produce enough product to fully do its job.

 “The future plans are to grow the testicular tissue, expand the cells and put it back into the patient,” Atala, told Motherboard in a story quoted in LatinosHealth. “But for a whole testicle, there is a very rich blood-vessel supply and that’s the challenge. We can make them small, but we’re working hard to make them larger.”

The U.S. Defense Department funds the work because of the number of soldiers who have had their reproductive ability damaged by war injuries. However, everyone on the research team predicts it will be many years before they can make fully functional organs to help out these war heroes.

Stem cell stories that caught our eye: reality check on chimeras, iPS cells for drug discovery and cell family history

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.

iPS cells becoming foot soldiers of drug discovery. Here at The Stem Cellar we write often about the power of iPS-type stem cells to model disease and accelerate drug development. This week provided a couple of strong reminders of the value of these induced pluripotent stem cells that researchers create by reprogramming any adult cell, usually skin or blood, into an embryonic stem cell-like state.

Researchers at Penn State University published work that used iPS cells from patients with Rett Syndrome to find a target for drug therapy for that severe form of autism spectrum disorder. After turning the stem cells into nerves they found those cells lacked a protein that is critical to the function of the neural transmitter GABA. That protein has now become a target for drug therapy. As a bonus for the field, the study, published in the Proceedings of the National Academy of Sciences, provided an explanation for why a drug already in clinical trials for Rett Syndrome might work. That drug is IGF1, insulin-like growth factor. The web site Medical News Today wrote up the research.

Later in the week an announcement popped up in my email for the two-day “inaugural” conference “Advances in iPS cell Technology for Drug Development Applications.” The field clearly has momentum. CIRM has funded a bank that will eventually house up to 3,000 cell lines relating to specific diseases. So far, 285 lines are available to researchers anywhere, 14 of them Autism spectrum lines, through the tissue banks at Coriell.

 

Tracking a cell’s family history. When cells divide their offspring can have a different identity from the mother cells. This occurs commonly in stem cells, as they mature into adult tissue, and in the immune system as cells respond to infections. Knowing the genetic details of how this happens could accelerate both stem cell science and our ability to understand and manipulate the immune system.

A team at MIT has taken us a step closer to this ability. They married a trendy new technique called single cell genetic analysis with a fluidic device that can isolate single cells in one chamber and daughter and grand daughter cells in subsequent chambers. In this case, they used single cell RNA-seq, the shorthand for sequencing. They wanted to know the differences between the cells in terms of genes that are actually active, and since the RNA representing a gene is only made when the gene is active, this provided a snapshot of each cell’s genetic identity.

Genetic Engineering News wrote about the work and quoted the lead author of the study Robert Kimmerling:

“Scientists have well-established methods for resolving diverse subsets of a population, but one thing that’s not very well worked out is how this diversity is generated. That’s the key question we were targeting: how a single founding cell gives rise to very diverse progeny.”

This new combined system should let researchers investigate how this happens. The MIT team started by looking at how one immune system cell can produce both the cells that attack and kill invaders and the cells that stick around and remember what the invaders looked like.

 

Human-animal chimeras, what are labs really doing. Antonio Regalado did a thorough piece in MIT Technology Review examining the work of the few labs around the country that are trying to grow human tissue in animal embryos—chimeras. He estimates that some 20 pig-human or sheep-human pregnancies have been established, but no one is letting those embryos grow more than a very few weeks. Their immediate goal is to better understand how the cells with different origins interact, not to breed chimeric animals.

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A pig at the UC Davis research center

One long-term goal is, for example, to grow a personalized new pancreas for diabetic patients who needs a new one of those insulin-producing organs. But no one in the field expects that to happen anytime soon. The process involves using modern genetic editing techniques to turn off the genes that would make a particular organ in the animal embryo, inserting human stem cells and hoping the growing embryo will hijack the genes for making the equivalent human organ, but not other human tissues.

The embryos examined so far have generally contained a very small amount of human DNA, less than one percent in a project at Stanford. So, probably not enough to give the animal human traits beyond the organ desired. Pablo Ross who has done some of the early work at the University of California, Davis explained the intent of those studies is “to determine the ideal conditions for generating human-animal chimeras.”

It is fascinating work and has great potential to alleviate organ shortages, but will require several more breakthroughs and much patience before that happens.

Stem cell stories that caught our eye: back repair, stem cell aging, babies for same sex couples, chimeras

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.

0c207-shutterstock_132771389Getting the right cells for back repair.  We often write that stem cells found in fat tissue can form bone, cartilage and other connective tissue. But that glosses over the fact that all those tissues come in many forms. A team in France has found a way to turn fat stem cells into the specific tissue found in the discs in our spine, that when deteriorated, leads to 40 percent of back pain.

The team at the French institute INSERM used two growth factors to turn stem cells from fat into cells called nucleus pulposus that make up the cushioning discs. Yahoo Finance ran a very short piece on the research that the team published in the journal Stem Cells.

 

Bone drug stops stem cell aging.  Doctors regularly use the drug zoledronate to improve the bone strength and extend the lives of patients with osteoporosis, but they don’t know exactly how it works. A team at the University of Sheffield in the U.K. pegged the drug’s role on reducing the natural DNA damage that occurs in the stem cells that build new bone. The drug in essence slows the aging of bone-forming stem cells.

They published their work in the journal Stem Cells and Health Medicine Network posted the university press release in which the authors speculate that the drug might have a similar impact on stem cells that are supposed to repair other tissues as well.

 “The drug enhances the repair of the damage in DNA occurring with age in stem cells in the bone. It is also likely to work in other stem cells too.”

The researchers suggest the drug could have a role in treating heart disease, muscle diseases and other age-related conditions.

 

Babies for same sex couples—not yet.  One recent journal publication contained no new scientific research yet generated many headlines, which often suggested an advance had been made that could allow same sex couples to have a completely biologically related baby. The original article, a review in the Journal of Law and the Biosciences, provided a look at the current state of the science of creating eggs and sperm from stem cells and an analysis of the ethical and policy implications of the work.

While the work is fairly advanced in mice, it is at very early stages in humans. Written by Sonia Suter of George Washington University in Washington, D.C., the review outlines potential benefits and risks of the process called in vitro gametogenesis (IVG). Medical News Today wrote a story from the university press release that quoted Suter:

“The ethical dilemmas about when and how such research should be done will be enormously challenging.”

Despite the many concerns, she suggests that with the strong support for other forms of assisted reproduction, eventually, IVG could be just another routine way to have a baby.

 

Chimeras can tell us about early development.  Another study that got a lot of press for the wrong reasons generated mouse embryos that contained tissue from human stem cells.  Those chimeras—organisms with cells from two species—were reported to prove the safety of pluripotent stem cells, those cells that can become any tissue in the body.

 

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Human cells (green) in a mouse embryo

The team placed human pluripotent stem cells, either reprogrammed iPS cells or embryonic stem cells, into early stage mouse embryos and saw them correctly turn into the three so-called germ layers that make up all parts of the body.  They only observed the tissue develop for two days, but during that time they saw no indication of tumors or inappropriate cell development.

However, as CIRM grantee Paul Knoepfler wrote in his The Niche blog the behavior of pluripotent stem cells in an early embryo, where you want them to behave like embryonic tissue, may not be relevant to how those cells would behave in an adult patient where it could be disastrous if the cells behaved in an embryonic fashion.

What the work by Victoria Mascetti and Roger Pederson of the University of Cambridge in the U.K. does provide is an elegant new tool to study early human embryonic development.

“Our finding that human stem cells integrate and develop normally in the mouse embryo will allow us to study aspects of human development during a window in time that would otherwise be inaccessible,” Mascetti said in a press release quoted in an article in The Scientist.

Stem cell stories that caught our eye: growing better bone, synthetic diaphragms, nerves that make music

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.

Image of the hydrogel containing mesenchymal stem cells.

Image of the hydrogel containing mesenchymal stem cells. Credit Harvard SEAS/Wyss Institute

A better way to grow bone.  The term hydrogel gets tossed around a lot in tissue engineering discussions. The porous, generally pliable materials used to hold stem cells in place when creating new tissue are far from uniform. They have highly variable properties. Making a version that mimics the natural environment where bone grows allowed a Harvard team to grow better quality bone and more of it than prior methods.

It turns out stem cells prefer to turn into bone when grown in an environment that readily relaxes in response to stress.  Think of Silly Putty instead of hard rubber.  When the Harvard team grew stem cells on a fast relaxing hydrogel, they saw an increased number of stem cells turn into bone and those cells continued to create more bone for weeks.

“This work both provides new insight into the biology of regeneration, and is allowing us to design materials that actively promote tissue regeneration,” said David Mooney, who led the team.

In a press release from the university picked up by Science Newsline, the researchers speculated that the findings should both enable better bone repair grafts, but also generate more research into how mechanical properties influence cell behavior.

Replacement diaphragms.  Paolo Macchiarini, the Italian scientist based at Sweden’s Karolinska Institute who created much news and a bit of controversy with surgeries to give patients lab-made windpipes, burst back into the news this week. This time with replacement diaphragms, that muscle in the abdomen critical for breathing. The tireless muscle is much more complex than the static windpipe, or trachea, and Macchiarini readily noted that his current work in rats is not nearly ready for patients.

When it is, it could be a life changer and maybe life saver for the one in 2,500 babies born with defects in their diaphragm. Using a technique similar to his work with the trachea, his team took stem cells from bone marrow and grew them on an artificial polymer scaffold.  When they transplanted sections of the synthetic diaphragm into a damaged diaphragm in the animals the sections of muscle beat in synchrony with the rest of the rat’s existing diaphragm. But Macchiarini notes they have no idea why this happened and until they do, the procedure will not be ready for the clinic.

“If you ask me why it happens, to be very honest I don’t know,” he told Alice Park writing for Time. “I can just say that we saw many proteins, extracellular matrix components that belong to the nervous system. So probably via this, the muscle was able to contract again.”

The team wants to refine the process by determining which of the stem cells are destined to become muscle.  The university put a bit more detail in a press release.

Video on synthetic windpipe.  Since Macchiarini’s early reports of giving patients new windpipes, or tracheas, several teams around the world have tried to refine the procedure. The East Coast TV station WFMZ did an easy-to-understand segment on one team’s efforts at Mount Sinai in New York City. So far, their work remains confined to lab animals, but hey hope to treat patients within 18 months.

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Lab grown trachea. Credit University College London.

Neural music synthesizer.  On first read, this one sounds a little far fetched. The headline says “world’s first neural synthesizer.” And even crazier, the artist did it with iPSC-type stem cells reprogrammed from his own skin.

The web magazine Fact ran a short piece in its music section. This is how the writer there described the synthesizer:

“Music is fed into the neurons as electrical stimulations and the neurons respond by controlling the synthesizer, creating an improvised post-human sound piece.”

Image from Guy Ben-Ary website.

Image from Guy Ben-Ary website.

It provides a bit more description and notes that the project by artist Guy Ben-Ary is supported by a creative Australia Fellowship award to develop a biologic self-portrait. The article does provide a link to Ben-Ary’s web site, which goes into great detail on every aspect of the project called “cellF.” He describes everything from the procedure for making the stem cells in Barcelona to how they are grown into nerve cells in special plates that can both send and receive signals to respond to the natural electro physiology of nerves.  He explains the special lab plates in this way:

“The dishes that host my ‘external brain’ (neural networks) consist of a grid of electrodes that can record the electric signals that the neurons produce and at the same time send stimulation to the neurons – essentially a read-and-write interface.”

The first concert using the synthesizer occurred October 4. A guest musician, a drummer from Tokyo, provided the sound that was converted to electrical stimulus for the nerves. The nerves responded by controlling the music synthesizer. The video documenting the performance is due to be posted later this month.

Stem cell stories that caught our eye: making vocal cords, understanding our brain and the age of donor cells matters

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.

Tissue engineered vocal cords. A report from the University of Wisconsin that researchers there had grown new vocal cords got quite a bit of play in the media including this piece on the NBC News web site. It caught my attention not so much because of what they had created, but rather because of the vivid example it provides of cells having a memory of their role and their ability to communicate with each other to function in that role.

In the rather simple experiment, the team took vocal fold tissue from patients who had their larynxes removed for reasons other than cancer. They then used a solution to separate the tissue into individual cells and seeded those cells onto collagen scaffolding. Within 14 days they had fully formed tissue. One of the researchers stated in a phone briefing that the cells knew what they should be doing:

“They’re effectively talking to each other and producing the structural proteins that make this special tissue capable of vibration,” said Brian Frey.

The team transplanted the tissue into a larynx from a deceased dog and was able to demonstrate that the cells could make sound. In the artificial lab setting it evidently sounded a bit like a Kazoo, but the researchers maintained that if transplanted into a human it could easily sound like a voice.

Never ending quest to understand our brain. We’ve known for some time that the gene NeuroD1 plays a critical role in the early development of the brain. Now work by researchers at the Institute of Molecular Biology in Mainz, Germany report that this one gene seems to be the master switch to creating the brain.

Neurons using NeuroD1

Cells in which NeuroD1 is turned on are reprogrammed to become neurons. Cell nuclei are shown in blue and neurons are shown in red

They used several popular new techniques to track the activity of NeuroD1 in living tissue. They found it turned on a large number of genes that act to maintain cells’ trajectory to become nerves. Another indication of NeuroD1’s Svengali role came when they realized that even after it is turned off, the other genes stay active and keep driving cells to become more brain tissue.

“Our research has shown how a single factor, NeuroD1, has the capacity to change the epigenetic landscape of the cell, resulting in a gene expression program that directs the generation of neurons,” wrote the investigators in the EMBO Journal.

A story in Genetic Engineering News describes the potential impact this finding could have on understanding brain development as well as in figuring out how to repair brain damage.

Age of donor cells matters. Stem cells in older individuals just don’t do their jobs as well as those in younger people. Now a team at the Miller School of Medicine in Miami has provided clear evidence that this difference matters when selecting donor stem cells—at least in the mice in this study.

The study, published in Translational Research, looked at the ability of mesenchymal stem cells (MSCs) to protect lungs from injury. HealthCanal picked up the institution’s press release that quoted one of the researchers.

“Donor stem cells from younger mice were effective in preventing damage when infused into older mice at the same time as a disease-causing agent,” said Marilyn K. Glassberg. “However, donor MSCs from older mice had virtually no effect.”

The issue becomes key when debating the merits of autologous cells (from the patient themselves) versus allogeneic cells (from donors). This study adds weight to the side that says for older patients choose allogeneic—and make sure the donor is young.

Stem cell stories that caught our eye: three teams refine cell reprogramming, also stem cell tourism

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.

Why stem cells in the lab don’t grow up right. A classic cartoon among stem cell fans shows a stem cell telling a daughter cell it can grow up to become anything, and in a living creature that is pretty much true. But in the lab those daughter cells often don’t behave and mature properly. This seems particularly true for stem cells made by reprogramming adult cells through the iPS cell technology.

Tissues, such as heart muscle grown in the lab from stem cells too often look and behave like heart tissue found in a growing embryo rather than like a mature adult. A team at Johns Hopkins decided the best way to solve this problem was to understand the differences between those heart tissues maturing in a lab and those grown naturally and to understand those differences at the molecular level. They looked at which molecular and genetic signaling pathways were turned on in each during development.

After studying 17,000 genes in 200 heart cell samples they found that the pathways in the lab-grown cells were like a map in which the roads don’t line up. Pathways that were supposed to be turned on were not and ones that were supposed to be blocked were open. In a university press release picked up by NewsMedical.net they explain that they now intend to look for ways to correct some of those misguided cellular pathways, in part by making the lab conditions better mimic normal growing conditions.

The result should be tissues grown for research that result in a more accurate model of disease and, potentially, better tissue for transplantation and repair.

Getting the cells needed faster. Pretty much everyone’s cell therapy wish list contains cells that genetically match the patient—to reduce the chance of immune system rejection—and often with the added feature of genetic modification to correct an in-born error. We have the technology to do this. You can use the iPS cell system to reprogram a patient’s adult cells into stem cells and use any number of gene modifying tools to correct the error. But the combined processes can take three months or more; time patients often don’t have.

Researchers at the University of Wisconsin’s Morgridge Institute and the Murdoch Children’s Research Institute in Australia have sped up that process to just two weeks. They found a way to do the stem cell conversion and the genetic correction at the same time and used the trendy new gene-editing tool, CRISPR, which is faster and simpler than other methods. Wisconsin’s stem cell pioneer James Thompson commented on the work led by Sara Howden:

James Thompson

James Thompson

“If you want to conduct therapies using patient-specific iPS cells, the timeline makes it hard to accomplish. If you add correcting a genetic defect, it really looks like a non-starter. You have to make the cell line, characterize it, correct it, then differentiate it to the cells of interest. In this new approach, Dr. Howden succeeded in combining the reprogramming and the gene correction steps together using the new Cas9/CRISPR technology, greatly reducing the time required.”

Howden discussed the work with Australian Broadcasting Corp and her institute issued a press release. In the release she noted than when iPS-based therapies become a reality, the faster method will be critical for certain patients such as children with severe immune deficiency or people with rapidly deteriorating vision.

Skipping the stem cell step. A team at Guangzhou Medical University created unusually pure heart muscle cells directly from skin samples without first turning them into iPS type stem cells. This so-called “direct reprogramming” has been accomplished for a few years, but mostly in nerve tissue and with much less efficiency. This team got 80 percent pure heart muscle.

Heart muscle cells created with traditional iPS cell reprogramming

Heart muscle cells created with traditional iPS cell reprogramming

They also avoided one of the potential problems with iPS technology. Most often, the reprogramming happens using viruses to carry genetic factors into adult cells. The Chinese team used proteins to do the reprogramming, which are much less likely to leave lasting, and potentially cancer-causing, changes in the cells.

“While additional research is needed to fully understand the properties of these cells, the results suggest a potentially safer method to generate cardiac progenitor cells for use as a regenerative therapy after a heart attack,” said Anthony Atala, Editor-in-Chief of STEM CELLS Translational Medicine, which published the work and released a press release picked up by BioSpace.

The research team noted one bit of needed work that reflected back to the first item in this post. They need to see if the new heart cells function like mature native cells and can interact properly with native cells if transplanted.

Stemming stem cell tourism. A pair of medical ethicists, one from Rice University in Houston and one from Wake Forest University in North Carolina, published a call for reforms in how stem cell clinical trials are designed and regulated. They say our system should encourage people to get therapy in the U.S. at regulated clinics rather than go overseas or to seek out unproven therapies here.

“The current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation and conduct of U.S. clinical trials,” the authors wrote. “Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the U.S. and within the clinical-trial process.”

The web portal MNT wrote an article on the paper based on a Rice press release. The piece notes that many of the same patients who came forward to secure state funding for stem cells like the voter initiative that created CIRM are now tired of waiting for therapies and are seeking out unproven therapies. The authors noted that the problems this causes, in addition to the risks for patients, include the lack of any systematic way to collect data on whether those therapies are really working.

“Policy should be aimed at bringing patients home and fostering responsible scientific research as well as access for patients,” they wrote. “This will require discussions about alternative approaches to the design and conduct of clinical trials as well as to how interventions are approved by the Food and Drug Administration.”

Stem cell stories that caught our eye: mini-brains in a dish, blood stem cells and state funded stem cell research

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.

Great review of brains in a dish. The veteran Associated Press science journalist Malcolm Ritter produced the most thorough overview I have seen of the recent spate of research projects that have grown “mini-brains” in lab dishes. He provides the perspective from the first report in 2013 to a recent, and as he noted, unconfirmed claim of a more complex ball of brain cells.

Alysson Muotri

Alysson Muotri

He uses CIRM grantee Alysson Muotri to discuss the value of modeling diseases with these pea-sized brains. In the case of this University of California, San Diego researcher that involves finding out how nerves in people with autism are different from those in other people. But Ritter does not leave the false impression that these very rudimentary clumps of cells—that each self-organize in slightly different ways—are functioning brains. He makes this point with great quote from Madeline Lancaster of the Medical Research Council in England:

“Lancaster compares the patchwork layout to an airplane that has one wing on top, a propeller at the back, the cockpit on the bottom and a wheel hanging off the side. ‘It can’t actually fly,’ she said. But ‘you can study each of the components individually and learn a lot about them.’”

Ritter also discusses the broader trend of creating various miniature “organoids” in the lab including a quote from CIRM grantee at the University of California, San Francisco, Arnold Kriegstein:

This overall approach “is a major change in the paradigm in terms of doing research with human tissues rather than animal tissues that are substitutes. … It’s truly spectacular.” Organoids “are poised to make a major impact on the understanding of disease, and also human development.”

Unfortunately, this AP piece did not get as broad a pick up as the wire service often achieves. But here is the version from the Seattle Times.

Throw out the textbook on blood stem cells. A new study suggests that the textbook roadmap showing blood stem cells slowly going down various paths to eventually produce specific adult blood cells may be like a faulty GPS system. In this case that voice saying “redirect” is the renown stem cell scientist John Dick of the University of Toronto.

plateletsDick’s research team showed that very early in the process the daughter cell of the stem cell is already committed to a specific adult cell, for instance a red blood cell or a platelet needed for clotting. Low cell counts for one of those cell is the most common cause for patients needing transfusions. Now, with these cell-specific progenitor cells discovered, it may be easier to generate those adult cells for therapy. The discovery will also help the research community better understand many blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases – from anemia, where there are not enough blood cells, to leukemia, where there are too many blood cells,” said Dick in a press release from the University affiliated Princess Margaret Cancer Center. “Think of it as moving from the old world of black-and-white television into the new world of high definition.”

The journal Science published the study today.

The power of states to fund stem cells. The Daily Beast published a good review of state efforts to fund stem cell research with the slightly mischievous title, “George W., Father of Stem-Cell Revolution.” It recounts how several states stepped into the breach after then President George W. Bush restricted stem cell research. The story originally ran in Kaiser Health News under a more subdued headline.

GWBush

The article states that today seven states offer some level of stem cell research funding. And the author asserts that as an engine for generating economic development and local scientific prestige “stem cell research for many states appears to be worth the investment.” We have to agree.

The story does retell some of the early criticisms of CIRM, but goes on to discuss some of our reforms and quotes our new president C. Randal Mills on the “systems-based agency” he is creating:

“We’re setting up continuous paths to move basic research to clinical trials. It’s like a train moving down a track, where each grant is the link to the next step down the line.”

The piece ends with a great forward-looking quote from Jakub Tolar, head of the University of Minnesota’s Stem Cell Institute:

“We started on drugs a hundred years ago. Then we went to monoclonal antibodies—biological. We are now getting ready to use cells as a third way of doing medicine. We are at a historical sweet spot.”