Stem cell stories that caught our eye: Some good news got a little overplayed on blindness and Alzheimer’s

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.

Stories on blindness show too much wide-eyed wonder. While our field got some very good news this week when Advanced Cell Technologies (ACT) published data on its first 18 patients treated for two blinding diseases, many of the news stories were a little too positive. The San Diego Union Tribune ran the story from Associated Press writer Maria Cheng who produced an appropriately measured piece. She led with the main point of this early-phase study—the cells implanted seem to be safe—and discussed “improved vision” in half the patients. She did not imply their sight came back to normal. Her third paragraph had a quote from a leading voice in the field Chris Mason of University College London:

“It’s a wonderful first step but it doesn’t prove that (stem cells) work.”

The ACT team implanted a type of cell called RPE cells made from embryonic stem cells. Those cells are damaged in the two forms of blindness tested in this trial, Stargardt’s macular dystrophy and age-related macular degeneration, the leading cause of blindness in the elderly. Some of the patients have been followed for three years after the cell transplants, which provides the best evidence to date that cells derived from embryonic stem cells can be safe. And some of the patients regained useful levels of vision, which with this small study you still have to consider other possible reasons for the improvement, but it is certainly a positive sign.

CIRM funds a team using a different approach to replacing the RPE cells in these patients and they expect to begin a clinical trial late this year

Stem cells create stronger bone with nanoparticles.   Getting a person’s own stem cells to repair bad breaks in their bones certainly seems more humane than hacking out a piece of healthy bone from some place else on their body and moving it to the damaged area. But our own stem cells often can’t mend anything more than minor breaks. So, a team from Keele University and the University of Nottingham in the U.K. laced magnetic nanoparticles with growth factors that stimulate stem cell growth and used external magnets to hold the particles at the site of injury after they were injected.

It worked nicely in laboratory models as reported in the journal Stem Cells Translational Medicine, and reported on the web site benzinga. Now comes the hard step of proving it is safe to test in humans

Stem cells might end chronic shortage of blood platelets. Blood platelets—a staple of cancer therapy because they get depleted by chemotherapy and radiation—too often are in short supply. They can only set on the shelf for five days after a donation. If we could generate them from stem cells, they could be made on demand, but you’d have to make many different versions to match various peoples’ blood type. The latter has been a bit of a moot point since no one has been able to make clinical grade platelets from stem cells.

plateletsA paper published today by Advanced Cell Technologies may have solved the platelet production hurdle and the immune matching all at once. (ACT is having a good week.) They produced platelets in large quantities from reprogrammed iPS type stem cells without using any of the ingredients that make many iPS cells unusable for human therapy. And before they made the platelets, they deleted the gene in the stem cells responsible for the bulk of immune rejection. So, they may have created a so-called “universal” donor.

They published their method in Stem Cell Reports and Reuters picked up their press release. Let’s see if the claims hold up.

Alzheimer’s in a dish—for the second time. My old colleagues at Harvard got a little more credit than they deserved this week. Numerous outlets, including the Boston Globe, picked up a piece by The New York Times’ Gina Kolata crediting them with creating a model of Alzheimer’s in a lab dish for the first time. This was actually done by CIRM-grantee Lawrence Goldstein at the University of California, San Diego, a couple years ago.

But there were some significant differences in what the teams did do. Goldstein’s lab created iPS type stem cells from skin samples of patients who had a genetic form of the disease. They matured those into nerve cells and did see increased secretion of the two proteins, tau and amyloid-beta, found in the nerves of Alzheimer’s patients. But they did not see those proteins turn into the plaques and tangles thought to wreak havoc in the disease. The Harvard team did, which they attributed, in part, to growing the cells in a 3-dimensional gel that let the nerves grow more like they would normally.

The Harvard team, however, started with embryonic stem cells, matured them into nerves, and then artificially introduced the Alzheimer’s-associated gene. They have already begun using the model system to screen existing drugs for candidates that might be able to clear or prevent the plaques and tangles. But they introduced the gene in such a way the nerve cells over express the disease gene, so it is not certain the model will accurately predict successful therapies in patients.

Don Gibbons

These Are the Cells You’re Looking for: Scientists Devise New Way to Extract Bone-Making Stem Cells from Fat

Buried within our fat tissue are stashes of stem cells—a hidden reservoir of cells that, if given the right cues, can transform into cells that make up bone, cartilage or fat. These cells therefore represent a much-needed store for regenerative therapies that rebuild bone or cartilage lost to disease or injury.

Finding cells that have bone-making potential is more efficiently done by looking at the genes they express (in this case, ALPL) than at proteins on their surface. The bone matrix being produced by cells is stained red in samples of cells that do not express ALPL (left), those that do express ALPL (right). [Credit: Darling lab/Brown University]

Finding cells that have bone-making potential is more efficiently done by looking at the genes they express (in this case, ALPL) than at proteins on their surface. The bone matrix being produced by cells is stained red in samples of cells that do not express ALPL (left), those that do express ALPL (right). The center image shows both types of cells prior to sorting [Credit: Darling lab/Brown University]

The only problem with these tucked-away cellular reservoirs, however, is identifying them and getting them out.

But now, researchers at Brown University have devised a unique method of identifying, extracting and then cultivating these bone-producing stem cells. Their results, published today in the journal Stem Cell Research & Therapy, seem to offer a much-needed alternative resource for growing bone.

Traditional methods attempting to locate and extract these stem cells focused on proteins that reside on the surface of the cells. Find the proteins, scientists reasoned, and you’ve found the cell.

Unfortunately, that method was not fool proof, and many argued that it wasn’t finding all the cells that reside in the fat tissue. So Brown scientists, led by Dr. Eric Darling found an alternative.

They knew that a gene called ALPL is an indicator of bone-making cells. If the gene is switched on, the cell has the potential to make bone. If it’s switched off, it does not. So Darling and his team devised a fluorescent marker, or tag, that stuck to the cells with activated ALPL. They then used a special machine to sort the cells: those that glowed went into one bucket, those that did not went into the other.

To prove that these ALPL-activated cells were indeed capable of becoming bone and cartilage, they then cultivated them for several weeks in a petri dish. Not only did they transform into the right cell types—they did so in greater numbers than cells extracted using traditional methods.

Hetal Marble, a graduate student in Darling’s lab and the paper’s first author, argues that tagging genes—rather than surface proteins—in order to distinguish and weed out cell types represents an important paradigm shift in the field. As he stated in a press release:

“Approaches like this allow us to isolate all the cells that are capable of doing what we want, whether they fit the archetype of what a stem cell is or is not. The paradigm shift is thinking about isolating populations that are able to achieve an end point rather than isolating populations that fit a strictly defined archetype.”

While their method is both precise and accurate, there is one drawback: it is slow.

Currently, it takes four days to tag, extract and cultivate the bone-making cells. In the future, the team hopes they can shorten this time frame so that they could perform the required steps within a single surgical session. As Darling stated:

“If you can take a patient into the OR, isolate a bunch of their cells, sort them and put them back in—that’s ideally where we’d like to go with this.”

Stories of Hope: Sickle Cell Disease

This week on The Stem Cellar we feature some of our most inspiring patients and patient advocates as they share, in their own words, their Stories of Hope.

Adrienne Shapiro pledged she would give her daughter Marissa the best possible life she could have—wearing herself out if necessary. Her baby girl had sickle cell disease, an inherited disorder in which the body’s oxygen-carrying red blood cells become crescent shaped, sticky, rigid, and prone to clumping—blocking blood flow. Doctors warned Adrienne that Marissa might not live to see her first birthday. When Marissa achieved that milestone, they moved the grim prognosis back a year, and then another year, and then another.

Adrienne has seen first hand how difficult it is to live with this blood disease.

Adrienne has lived through several generations of the inherited blood disease.

Adrienne worked tirelessly to help Marissa. “I was constantly asking questions,” Shapiro says. And for a long time, it worked.

However, things began to unravel for Marissa as she reached adulthood. A standard treatment for sickle cell disease—and the excruciating pain caused by blocked blood vessels—is regular blood transfusions. A transfusion floods the body with healthy, round red blood cells, lowering the proportion of the deformed, ‘sickle-shaped’ cells. But when she was 20, a poorly matched blood transfusion triggered a cascade of immune problems. Later, surgery to remove her gall bladder set off a string of complications and her kidneys shut down temporarily. After that, her immune system couldn’t take any more insults. Now, at age 36, she’s hypersensitive.

“She can’t be transfused. She can’t even have tape next to her skin without her body reacting,” Adrienne said.

Pain control is the newest and continuing nightmare. Adrienne tells harrowing stories of long waits in hospital emergency rooms while her daughter suffers, followed by maddening arguments with staff reluctant to provide enough drugs to control the intense pain when her daughter is finally admitted.

“When she was a kid, everyone wanted to make her feel good,” Adrienne says. “But when we moved from the pediatric side to the adult side, they treated her as a drug seeker and me as an enabler. It’s such a slap in the face.”

For Adrienne, the story is all too familiar. She is the third generation in her family with a sickle cell child. Another daughter, Casey Gibson, does not have the disease but carries the sickle cell mutation, meaning she could pass it to a child if the father also has the trait. One in 500 African Americans has sickle cell disease, as do 1 in 36,000 Hispanic people.

There is only one sure way to stop this story from repeating for generations to come, Adrienne says, and that’s research. She believes stem cell science will be the answer.

“I’ve been waiting for this science to get to the point where it had a bona fide cure, something that worked. Now we’re actually nearing clinical trials. It’s so close.”

In fact a CIRM-funded project led by Don Kohn, M.D. at UCLA aims to start trials in 2014. Kohn and his team intend to remove bone marrow from the patient and fix the genetic defect in the blood-forming stem cells. Then those cells can be reintroduced into the patient to create a new, healthy blood system.

“Stem cells are our only hope,” Adrienne continues, “It’s my true belief that I’m going to be the last woman in my family to have a child with sickle cell disease. Marissa’s going to be the last child to suffer, and Casey is going to be the last one to fear. Stem cells are going to fix this for us and many other families.”

For more information about CIRM-funded sickle cell disease research, visit our Sickle Cell Disease Fact Sheet. You can read more about Adrienne’s Story of Hope on our website.

CIRM-Funded Scientists Test Recipe for Building New Muscles

When muscles get damaged due to disease or injury, the body activates its reserves—muscle stem cells that head to the injury site and mature into fully functioning muscle cells. But when the reserves are all used up, things get tricky.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

This is especially the case for people living with muscle diseases, such as muscular dystrophy, in which the muscle degrades at a far faster rate than average and the body’s reserve stem cell supply becomes exhausted. With no more supply from which to draw new muscle cells, the muscles degrade further, resulting in the disease’s debilitating symptoms, such as progressive difficulty walking, running or speaking.

So, scientists have long tried to find a way to replenish the dwindling supply of muscle stem cells (called ‘satellite cells’), thus slowing—or even halting—muscle decay.

And now, researchers at the Sanford-Burnham Medical Research Institute have found a way to tweak the normal cycle, and boost the production of muscle cells even when supplies appear to be diminished. These findings, reported in the latest issue of Nature Medicine, offer an alternative treatment for the millions of people suffering not only from muscular dystrophy, but also other diseases that result in muscle decay—such as some forms of cancer and age-related diseases.

In this study, Sanford-Burnham researchers found that introducing a particular protein, called a STAT3 inhibitor, into the cycle of muscle-cell regeneration could boost the production of muscle cells—even after multiple rounds of repair that would otherwise render regeneration virtually impossible.

The STAT3 inhibitor, as its name suggests, works by ‘inhibiting,’ or effectively neutralizing, another protein called STAT3. Normally, STAT3 gets switched on in response to muscle injury, setting in motion a series of steps that replenishes muscle cells.

In experiments first in animal models of muscular dystrophy—and next in human cells in a petri dish—the team decided to modify how STAT3 functions. Instead of keeping STAT3 active, as would normally occur, the team introduced the STAT3 inhibitor at specific times during the muscle regeneration process. And in so doing, noticed a significant boost in muscle cell production. As Dr. Alessandra Sacco, the study’s senior author, stated in a news release:

“We’ve discovered that by timing the inhibition of STAT3—like an ‘on/off’ light switch—we can transiently expand the satellite cell population followed by their differentiation into mature cells.”

This approach to spurring muscle regeneration, which was funded in part by a CIRM training grant, is not only innovative, but offers new hope to a disease for which treatments have offered little. As Dr. Vittorio Sartorelli, deputy scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), stated:

“Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process. A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”

Sacco and her colleagues are encouraged by these results, and plan to explore their findings in greater detail—hopefully moving towards clinical trials:

“Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans.”

Stem Cell Stories that Caught our Eye: What’s the Best Way to Treat Deadly Cancer, Destroying Red Blood Cells’ Barricade, Profile of CIRM Scientist Denis Evseenko

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 vs. Drugs for Treating Deadly Cancer. When dealing with a potentially deadly form of cancer, choosing the right treatment is critical. But what if that treatment also poses risks, especially for older patients? Could advances in drug development render risky treatments, such as transplants, obsolete?

That was the focus of a pair of studies published this week in the New England Journal of Medicine, where a joint Israeli-Italian research team investigated the comparative benefits of two different treatments for a form of cancer called multiple myeloma.

Multiple myeloma attacks the body’s white blood cells. While rare, it is one of the most deadly forms of cancer—more than half of those diagnosed with the disease do not survive five years after being diagnosed. The standard form of treatment is usually a stem cell transplant, but with newer and better drugs coming on the market, could they render transplants unnecessary?

In the twin studies, the research team divided multiple myeloma patients into two groups. One received a combination of stem cell transplant and chemotherapy, while the other received a combination of drugs including melphalan, prednisone and lenalidmomide. After tracking these patients over a period of four years, the research team saw a clear advantage for those patients that had received the transplant-chemotherapy treatment combination.

To read more about these twin studies check out recent coverage in NewsMaxHealth.

Breaking Blood Cells’ Barricade. The process whereby stem cells mature into red blood cells is, unfortunately, not as fast as scientists would like. In fact, there is a naturally occurring barrier that keeps the production relatively slow. In a healthy person this is not necessarily a problem, but for someone in desperate need of red blood cells—it can prove to be very dangerous.

Luckily, scientists at the University of Wisconsin-Madison have found a way to break through this barrier by switching off two key proteins. Once firmly in the ‘off’ position, the team could boost the production of red blood cells.

These findings, published in the journal Blood, are critical in the context of disease anemia, where the patient’s red blood cell count is low. They also may lead to easier methods of stocking blood banks.

Read more about this exciting discovery at HealthCanal.

CIRM Scientist on the Front Lines of Cancer. Finally, HealthCanal has an enlightening profile of Dr. Denis Evseenko, a stem cell scientist and CIRM grantee from the University of California, Los Angeles (UCLA).

Born in Russia, the profile highlights Evseenko’s passion for studying embryonic stem cells—and their potential for curing currently incurable diseases. As he explains in the article:

“I had a noble vision to develop progressive therapies for the patient. It was a very practical vision too, because I realized how limited therapeutic opportunities could be for the basic scientist, and I had seen many great potential discoveries die out before they ever reached the clinic. Could I help to create the bridge between stem cells, research and actual therapeutics?”

Upon arriving at UCLA, Evseenko knew he wanted to focus this passion into the study of degenerative diseases and diseases related to aging, such as cancer. His bold vision of bridging the gap between basic and translational research has earned him support not only from CIRM, but also the National Institutes of Health and the US Department of Defense, among others. Says Evseenko:

“It’s my hope that we can translate the research we do and discoveries we make here to the clinic to directly impact patient care.”

Body’s own Healing Powers Could be Harnessed to Regrow Muscle, Wake Forest Study Finds

Imagine being able to repair muscle that had been damaged in an injury, not by transplanting new muscle or even by transplanting cells, but rather simply by laying the necessary groundwork—and letting the body do the rest.

The ability for the human body to regenerate tissues lost to injury or disease may still be closer to science fiction than reality, but scientists at the Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, have gotten us one big step closer.

Reporting in the latest issue of the journal Acta Biomaterialia, Dr. Sang Jin Lee and his research team describe their ingenious new method for regrowing damaged muscle tissue in laboratory rodents—by supercharging the body’s own natural restorative abilities. As Lee explained in a news release:

“Working to leverage the body’s own regenerative properties, we designed a muscle-specific scaffolding system that can actively participate in functional tissue regeneration. This is a proof-of-concept study that we hope can one day be applied to human patients.”

Normally, the body’s muscles—as well as the majority of organs—sit atop a biological ‘scaffold’ created by a matrix of molecules secreted by surrounding cells. This scaffold gives the organs and muscle their three-dimensional structure.

Scientists have identified a protein that may help spur 'in body' muscle regeneration.

Scientists have identified a protein that may help spur ‘in body’ muscle regeneration.

As of right now, if doctors want to replace damaged muscle they have one of two options: either surgically transfer a muscle segment from one part of the body to the other, or engineer replacement muscle tissue in the lab from a biopsy. Both methods, while doable, are not ideal. In the first, you are reducing the strength of the donor muscle; in the second, you have the added challenge of standardizing the engineered cells so that they will graft successfully.

So, Lee and his team focused on a third way: coaxing the body’s own supply of adult stem cells—which are tissue specific and normally used for general small-scale maintenance—to rebuild the damaged muscle from within. Said Lee:

“Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration.”

In this study, the researchers developed a method to do just that in the laboratory animals. First, they implanted a new cellular scaffold into the rodents’ legs. After several weeks, they removed the scaffold to see whether any cells had latched on of their own accord.

Interestingly, the team found that without any additional manipulation, the scaffold had developed a network of blood vessels within just four weeks after implanting. They also observed the presence of some early-stage muscle cells. What the researchers wanted to do next was find a way to boost what they already observed naturally.

To do so, they tested whether proteins—previously known to be involved in muscle development—could boost the speed and amount of recruitment of muscle stem cells to the scaffold.

After a series of experiments, they found a leading candidate: a protein called insulin-like growth factor 1, or IGF-1. And when they injected IGF-1 into the newly-implanted scaffolds the difference was remarkable. These scaffolds had about four times as many cells when compared to the plain scaffolds. As Lee explained:

“The protein effectively promoted cell recruitment and accelerated muscle regeneration.”

The real work now begins, added Lee, whose team will now take their research to larger animal models, such as pigs, to see whether their technique can work on a far grander scale.

Stem cell stories that caught our eye: Willie Nelson’s contribution to muscular dystrophy, cell fate maps and funding

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.

Cell fate map can show quality of cells.
The phrase “there is more than one way to skin a cat” fits much of science. It is quite true for using stem cell science to generate a needed type of adult cell to repair damaged tissue. The most traditional way, directing early stem cells, the ones called pluripotent, to mature into the desired tissue is often cumbersome and has the potential of leaving behind a few of those early cells that could cause a tumor. More recently, many teams have been starting with one type of adult tissue and reprogramming them to directly convert into a different adult tissue without passing through that potentially tumor causing state. But we have not had a good way to measure which route produces the higher quality cells—which one yield cells most like those in our body.

credit: Samantha Morris, Ph.D./Boston Children's Hospital

credit: Samantha Morris, Ph.D./Boston Children’s Hospital

Some of the biggest potential differences between cells grown in a dish and those in us, is the state of the various genetic switches that turn our genes on and off. Now, a team at Boston Children’s Hospital, the Wyss Institute at Harvard and Boston University has developed a computer algorithm to compare our natural cells to various types of cells grown in the lab.

Many in the field had hoped that the direct conversion of adult cells to other cell types would prove to be the way to go. Unfortunately, the computer program showed that those cells were not nearly as good at mimicking natural cells as cells matured from early stem cells were. However, the team suggests their system points to ways to improve direct conversion. The researchers published two paper on the system they are calling CellNet in the journal Cell August 14 and Genetic Engineering and Biotechnology News did a nice write up of the work.

Willie Nelson advances stem cells for muscular dystrophy.
Really! No, Willie is not in the lab, but he was named an honorary member of the lab and had an endowed chair held by the lab director named for him. He had performed at a concert to raise money to fund the work at UT Southwestern Medical Center in Dallas and the university decided to honor him with the named chair.

In the current paper the lab used the most trendy form of gene modification out there right now, called CRISPR. Researchers are excited about the technology because it can specifically go into our DNA and permanently cut out a mutation. Then our natural genetic machinery can go about making the correct gene. In this case they used it to cut out the error that caused Duchenne muscular dystrophy in a mouse model. After the correction, the mice grew new muscle and got stronger.

The CRISPR technology needs some refinements before it would be ready for use in humans, but the team is working on that along with many others around the country. Their goal: correct the error in patient muscle stem cells so that they can produce a lifetime supply of healthy muscle. The journal Science published their work online August 14 and the HealthCanal website picked up the university press release.

Scientists need to talk to the public. The director of the National Institutes of Health, Francis Collins, visited the University of Washington this week and delivered a message straight from my personal soapbox: Funding for research is in jeopardy and the only way it will be salvaged is for researchers to get more involved in outreach to the public. The Seattle Times quoted him as saying:

“I think it’s at a particularly crucial juncture. If there was a moment to kind of raise consciousness, this is kind of the moment to do that.”

He noted that the chances of a research proposal submitted to NIH getting funded dropped from 40 percent in 1979 to 16 percent now, saying “we’re leaving half the good science on the table.” Part of the solution he suggested was for scientists to get out to Rotary clubs, high school classrooms, and any other public speaking opportunity.

“It seems to me that we all have to spend more of our time, perhaps, as ambassadors for science literacy — trying to explain what we do and why it matters.”

Don Gibbons

Revealing the Invisible: Scientists Uncover the Secret Ingredient to Making Blood-Forming Stem Cells

They are among the most versatile types of stem cell types in the body. They live inside bone marrow and in the blood of the umbilical cord. They can be used to treat deadly cancers such as leukemia (Leukemia Fact Sheet) as well as many blood disorders. But no one really understood the details of how they were made.

How are blood stem cells made? Australian scientists have uncovered a missing ingredient.

How are blood stem cells made? Australian scientists have uncovered a missing ingredient.

That is, until scientists at the Australian Regenerative Medicine Institute devised an ingenious way to view the formation of these hematopoetic stem cells (HSC’s) in unprecedented detail. And in so doing, found the missing ingredient that may make it possible to grow fully functioning versions of these cells in the lab—opening the door to treating a wide range of blood and immune disorders. Attempts to grow these in the past have resulted in immature versions more like those found in a fetus than those in an adult.

One of the study’s senior authors, Dr. Peter Currie, even goes so far as to say this discovery represents a ‘Holy Grail’ for the field. As he explained in today’s news release:

“HSCs are one of the best therapeutic tools at our disposal because they can make any blood cell in the body. Potentially we could use these cells in may more ways than current transplantation strategies to treat serious blood disorders and diseases, but only if we can figure out how they are generated in the first place.”

Fortunately, this new study—published today in the journal Nature—brings researchers closer to that goal.

Using high-resolution microscopic imaging techniques, Currie and his team filmed the development of a zebra fish embryo—with a particular focus on HSCs. When they played back the video, the team saw something that no one had noticed before. In order for HSCs to develop properly, they needed a little support from another cell type known as endotomes. As Currie explained:

“Endotome cells act like a comfy sofa for pre-HSCs to snuggle into, helping them progress to become fully fledged [HSCs]. Not only did we identify some of the cells and signals required for HSC formation, we also pinpointed the genes required for endotome formation in the first place.”

It appears that this unique relationship between endotomes and HSCs is key to HSC formation, a process that had for so long evaded researchers. But armed with this newfound knowledge, the team could one day produce different types of blood cells ‘on demand’—and potentially treat many types of blood disorders. This has been such a tough nut to crack with such great potential CIRM convened an international panel of experts to produce a whitepaper on the issue.

The team’s immediate next steps, according to Currie, are to pinpoint the molecular switches themselves (within endotomes and HSCs) that trigger the production of these stem cells. And while these results are preliminary, he is cautiously optimistic about the potential power to treat a variety of illnesses:

“Potentially, it’s imaginable that you could even correct genetic defects in cells and then transplant them back into the body.”

Creaky Cell Machinery Affects the Aging Immune System, CIRM-Funded Study Finds

Why do our immune systems weaken over time? Why are people over the age of 60 more susceptible to life-threatening infections and many forms of cancer? There’s no one answer to these questions—but scientists at the University of California, San Francisco (UCSF), have uncovered an important mechanism behind this phenomenon.

Reporting in the latest issue of the journal Nature, UCSF’s Dr. Emmanuelle Passegué and her team describe how blood and immune cells must be continually replenished over the lifetime of an organism. As that organism ages the complex cellular machinery that churns out new cells begins to falter. And when that happens, the body can become more susceptible to deadly infections, such as pneumonia.

As Passegué so definitively put it in a UCSF news release:

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies.”

The research team, which examined this mechanism in old mice, focused their efforts on hematopoetic stem cells—a type of stem cell that is responsible for producing new blood and immune cells. These stem cells are present throughout an organism’s lifetime, regularly dividing to preserve their own numbers.

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

But in an aging organism, these cells’ ability to generate new copies is not as good as it used to be. When the research team dug deeper they found a key bit of cellular machinery, called the mini-chromosome maintenance helicase, breaks down. When that happens, the DNA inside the cell can’t replicate itself properly—and the newly generated cell is not running on all cylinders.

One of the first things that these old stem cells lose as a result is their ability to make B cells. B cells, a key component of the immune system, normally make antibodies that fight infection. As B cell numbers dwindle in an aging organism, so too does their ability to fight infection. As a result the organism’s risk for contracting dangerous illnesses skyrockets.

This research, which was funded in part by CIRM, not only informs what goes wrong in an aging organism at the molecular level, but also points to new targets that could keep these stem cells functioning at full capacity, helping promote so-called ‘healthy aging.’ As Passegué added:

“Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning.”

ISSCR 2014: Tony Atala, Jason Burdick and the Power of Tissue Engineering

The progress in tissue engineering in just the past two decades has been like the construction industry moving from simple lean-to structures to homes with plumbing, heating and cooling systems. We are not yet ready to build a high-rise—think of a beating functioning heart—but we are making major strides toward that goal.

One of the founders of the field, Wake Forest’s Dr. Tony Atala, led off this morning plenary session at the annual meeting of the International Society for Stem Cell Research. He started trying to build simple organs in 1990. His talk nicely mapped his progress through four levels of complexity of structure.

Tony Atala speaks about tissue engineering in a 2011 TED talk (credit: Wikipedia)

Tony Atala speaks about tissue engineering in a 2011 TED talk (credit: Wikipedia)

The first level, accomplished by a few teams, was our largest organ, skin, which is relatively simple because it is flat. Next, came simple hollow organs like blood vessels and the urethra that carries urine from the bladder. He followed that with more complex hollow organs, first the bladder and more recently the vagina. Last up were complex solid organs: the heart and the penis. He expects to begin clinical trials with the latter soon, which is eagerly anticipated by our military dealing with the aftermath IED explosive injuries from the wars in Iraq and Afghanistan.

He noted that researchers in the field quickly learned that just throwing cells on scaffolds and hoping they knew what to do was not enough in most cases. They need to grow blood vessels so they can get nourishment and communicate with their surroundings and they often have to make multiple cell types. His own work here benefited from a bit of geographic serendipity. His lab at the time was on the same floor as Judah Folkman’s at Harvard affiliated Children’s Hospital. Folkman is the father of the field of angiogenesis, the art of growing blood vessels.

Atala showed slides comparing injecting cells where you need new muscle, to cells plus scaffold, and finally to the two combined with a vessel growth factor. The three-way combo far outperformed the others. He published his first study using this technique for a hollow simple organ, the urethra, in 2011. At that point his patients had been living with the functional new organ for six years. They work and last.

Researchers almost always place a cell-scaffold complex in a soup of nutrients and growth factors called a bioreactor before implanting it. But at the time of implant, the organ is not mature. Atala said the body acts like a “finishing bioreactor” to fill out and strengthen the organ, which becomes fully mature around six months after implant. He showed images of this in-body growth in his first patients who had been born without a complete vagina and were given a fully functioning organ. He just published that study two months ago, eight years after the implants in order to make sure they stayed functional over time.

He then showed his animal model work creating a penis in rabbits. Being a highly vascular organ it required much more structure. He used a donor organ that had all its cells chemically washed away to leave just the intracellular scaffold. This structure helped guide the blood vessel growth and the rabbits succeeded in mating and having offspring.

His lab has begun early stage work for both liver and heart. They have created miniature livers about the size of a half dollar that are able to produce the appropriate proteins and metabolize drugs. They have used a 3-D printer to build two chambers of a heart that are able to beat in a dish, but their structure has not been stable. So, he noted much more work lies ahead for complex organs.

The second speaker, Jason Burdick from the University of Pennsylvania, concentrated on making better scaffolds for the stem cells, which can have three enhanced properties:

  1. they can be instructive, they can tell cells what to do;
  2. they can be dynamic, they can react to their environment and the cells around them;
  3. they can lead to heterogeneity, they can provide varied instructions so you get the different cell types that you need for a complex tissue.

He discussed two examples, the first was growing better cartilage (as he joked, for injured World Cup soccer players). One problem with early gels used as scaffold was they held the cells individually apart from each other limiting their ability to communicate with each other. This cell-to-cell cross talk is key to tissue maturation. He showed how you could chemically alter the gel to enhance this communication. He also showed how you could implant the gels with microspheres loaded with growth factors to deliver instructions to the cells.

Burdick’s second example focused on minimizing injury after an induced heart attack in rodents. But instead of loading the gel with cells, they loaded it with microspheres that release chemicals that summons the stem cells waiting quietly in reservoirs in all of us. They saw sustained release of the chemicals for 21 days and significant improvement in heart function.

But he closed with a fun twist. The first heart experiment used a strict time-release formulation. He said it would be much better if the chemicals were released at the points the heart needs it the most. So, he is working on a system that releases the chemical based on the levels of an enzyme the heart makes when it is injured. He is hoping this right-amount-at-the-right-time formula will be even better.

We have a short video of the highlights of a workshop we held on tissue engineering that you can watch to get a better feel for where the field is going.

Don Gibbons