Dr Bryant Villeponteau the formulator of Stem Cell 100 and other Life Code nutraceuticals was recently interviewed by Dr Mercola who owns the largest health web site on the internet. Dr. Villeponteau is also the author of Decoding Longevity an new book which will be released during December. He is a leading researcher in novel anti-aging therapies involving stem cells an area in which he has been a pioneer for over three decades.

Stem cell technology could have a dramatic influence on our ability to live longer and replace some of our failing parts, which is the inevitable result of the aging process. With an interest in aging and longevity, Dr. Villeponteau started out by studying developmental biology. “If we could understand development, we could understand aging,” he says. Later, his interest turned more toward the gene regulation aspects. While working as a professor at the University of Michigan at the Institute of Gerontology, he received, and accepted, a job offer from Geron Corporation—a Bay Area startup, in the early ‘90s.

“They were working on telomerase, which I was pretty excited about at the time. I joined them when they first started,” he says. “We had an all-out engagement there to clone human telomerase. It had been cloned in other animals but not in humans or mammals.”

If you were to unravel the tip of the chromosome, a telomere is about 15,000 bases long at the moment of conception in the womb. Immediately after conception, your cells begin to divide, and your telomeres begin to shorten each time the cell divides. Once your telomeres have been reduced to about 5,000 bases, you essentially die of old age.

“What you have to know about telomerase is that it’s only on in embryonic cells. In adult cells, it’s totally, for the most part, turned off, with the exception of adult stem cells,” Dr. Villeponteau explains. “Adult stem cells have some telomerase – not full and not like the embryonic stem cells, but they do have some telomerase activity.”

Most of the research currently being done, both in academia and industrial labs, revolves around either embryonic stem cells, or a second type called induced pluripotent stem cells (iPS). Dr. Villeponteau, on the other hand, believes adult stem cells are the easiest and most efficient way to achieve results.

That said, adult stem cells do have their drawbacks. While they’re your own cells, which eliminates the problem of immune-related issues, there’s just not enough of them. Especially as you get older, there are fewer and fewer adult stem cells, and they tend to become increasingly dysfunctional too. Yet another hurdle is that they don’t form the tissues that they need to form…

To solve such issues, Dr. Villeponteau has created a company with the technology and expertise to amplify your adult stem cells a million-fold or more, while still maintaining their ability to differentiate all the different cell types, and without causing the cells to age. Again, it is the adult stem cell’s ability to potentially cure, or at least ameliorate, many of our age-related diseases by regenerating tissue that makes this field so exciting.

Dr Villeponteau believes you can add many years, likely decades, to your life simply by eating right, exercising (which promotes the production of muscle stem cells, by the way) and living an otherwise clean and healthy lifestyle. Extreme life extension, on the other hand, is a different matter.

His book, Decoding Longevity, covers preventive strategies to prolong your life, mainly diet, exercise, and supplements. A portion of the book also covers future developments in the area of more radical life extension, such as stem cell technology.

If you would like to read the entire interview here is a link to the text version:

Transcript of Interview With Dr. Bryant Villeponteau by Dr. Joseph Mercola

lroot on June 28th, 2017

Now researchers have found a way not just to stop, but, reverse the aging process. The key is something called a telomere. We all have them. They are the tips or caps of your chromosomes. They are long and stable in young adults, but, as we age they become shorter, damaged and frayed. When they stop working we start aging and experience things like hearing and memory loss.

In a recent study published in the peer reviewed journal Nature scientists took mice that were prematurely aged to the equivalent of 80-year-old humans, added an enzyme and essentially turned their telomeres back on. After the treatment they were the physiological equivalent of young adults. You can see the before and after pictures in the videos above. Brain function improved, their fertility was restored it was a remarkable reversal of the aging process. In the top video the untreated mouse shows bad skin, gray hair and it is balding. The mouse with it’s telomeres switched back on has a dark coat color, the hair is restored and the coat has a nice healthy sheen to it. Even more dramatic is the change in brain size. Before treatment the aged mice had 75% of a normal size brain like a patient with severe Alzheimers. After the telomeres were reactivated the brain returned to normal size. As for humans while it is just one factor scientists say the longer the telomeres the better the chances for a more graceful aging.

The formal study Telomere dysfunction induces metabolic and mitochondrial compromise was published in Nature.

Additional information published by Harvard can be found in the following articles.

Scientists Find Root Molecular Cause of Declining Health in the Old

Decoding Immortality – Smithsonian Channel Video about the Discovery of Telomerase

While scientists are not yet able to accomplish the same results in humans we believe we have developed a nutraceutical to help prolong youth and possibly extend life until age reversal therapy for humans becomes available.

lroot on June 28th, 2017

New evidence that adult stem cells are critical to human aging has recently been published on a study done on a super-centenarian woman that lived to be 115 years. At death, her circulating stem cell pool had declined to just two active stem cells from stem cell counts that are typically more than a thousand in younger adults. Super-centenarians have survived all the normal diseases that kill 99.9% of us before 100 years of age, so it has been a mystery as to what actually kills these hardy individuals. This recent data suggest that stem cell decline may be the main contributor to aging. If so, stabilizing stem cells may be the best thing one can do to slow your rate of aging.

There are many theories of aging that have been proposed. For example, damage to cells and tissues from oxidative stress has been one of the most popular fundamental theories of aging for more than half a century. Yet antioxidant substances or genes that code antioxidant enzymes have proven largely ineffective in slowing aging when tested in model animals. Thus, interest by scientists has shifted to other hypotheses that might provide a better explanation for the slow declines in function with age.

Stem cells provide one such promising mechanism of aging. Of course, we all know that babies are young and vigorous, independent of the age of their parents. This is because adults have embryonic stem cells that can generate young new cells needed to form a complete young baby. Indeed, these embryonic stem cells are the product of continuously evolving stem cell populations that go back to the beginning of life on earth over 3.5 billion years ago!

In adults, the mostly immortal embryonic stem cells give rise to mortal adult stem cells in all the tissues of the body. These adult stem cells can regenerate your cells and tissues as they wear out and need replacement. Unfortunate, adult stem cells also age, which leads to fewer cells and/or loss of function in cell replacement. As functional stem cells decline, skin and organs decline with age.

Blood from world’s oldest woman suggests life limit

Time Magazine: Long-Life Secrets From The 115-Year-Old Woman

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Abstract
The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

lroot on June 28th, 2017

Infinity Symbol

Emma Morano passed away last April. At 117 years old, the Italian woman was the oldest known living human being.

Super centenarians, such as Morano and Jeanne Calment of France, who famously lived to be 122 years old, continue to fascinate scientists and have led them to wonder just how long humans can live. A study published in Nature last October concluded that the upper limit of human age is peaking at around 115 years.

Now, however, a new study in Nature by McGill University biologists Bryan G. Hughes and Siegfried Hekimi comes to a starkly different conclusion. By analyzing the lifespan of the longest-living individuals from the USA, the UK, France and Japan for each year since 1968, Hekimi and Hughes found no evidence for such a limit, and if such a maximum exists, it has yet to be reached or identified, Hekimi says.

Far into the foreseeable future

“We just don’t know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans, could continue to increase far into the foreseeable future,” Hekimi says. Many people are aware of what has happened with average lifespans. In 1920, for example, the average newborn Canadian could expect to live 60 years; a Canadian born in 1980 could expect 76 years, and today, life expectancy has jumped to 82 years. Maximum lifespan seems to follow the same trend.

It’s impossible to predict what future lifespans in humans might look like, Hekimi says. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push back the upper limit.

“It’s hard to guess,” Hekimi adds. “Three hundred years ago, many people lived only short lives. If we would have told them that one day most humans might live up to 100, they would have said we were crazy.”

Reference: Bryan G. Hughes, Siegfried Hekimi. Many possible maximum lifespan trajectories. Nature, 2017; 546 (7660): E8 DOI: 10.1038/nature22786

Bone Fracture

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, the pioneering method of combining ultrasound, stem cell and gene therapies could eventually replace grafting as a way to mend severely broken bones.

“We are just at the beginning of a revolution in orthopedics,” said Dan Gazit, PhD, DMD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. “We’re combining an engineering approach with a biological approach to advance regenerative engineering, which we believe is the future of medicine.”

Gazit was the principal investigator and co-senior author of the research study, published in the journal Science Translational Medicine.

More than 2 million bone grafts, frequently necessitated by severe injuries involving traffic accidents, war or tumor removal, are performed worldwide each year. Such injuries can create gaps between the edges of a fracture that are too large for the bone to bridge on its own. The grafts require implanting pieces from either the patient’s or a donor’s bone into the gap.

“Unfortunately, bone grafts carry disadvantages,” said Gazit, a professor of surgery at Cedars-Sinai. “There are huge unmet needs in skeleton repair.”

One problem is that enough healthy bone is not always available for repairs. Surgeries to remove a bone piece, typically from the pelvis, and implant it can lead to prolonged pain and expensive, lengthy hospitalizations. Further, grafts from donors may not integrate or grow properly, causing the repair to fail.

The new technique developed by the Cedars-Sinai-led team could provide a much-needed alternative to bone grafts.

In their experiment, the investigators constructed a matrix of collagen, a protein the body uses to build bones, and implanted it in the gap between the two sides of a fractured leg bone in laboratory animals. This matrix recruited the fractured leg’s own stem cells into the gap over a period of two weeks. To initiate the bone repair process, the team delivered a bone-inducing gene directly into the stem cells, using an ultrasound pulse and microbubbles that facilitated the entry of the gene into the cells.

Eight weeks after the surgery, the bone gap was closed and the leg fracture was healed in all the laboratory animals that received the treatment. Tests showed that the bone grown in the gap was as strong as that produced by surgical bone grafts, said Gadi Pelled, PhD, DMD, assistant professor of surgery at Cedars-Sinai and the study’s co-senior author.

“This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal’s own stem cells can effectively be used to treat nonhealing bone fractures,” Pelled said. “It addresses a major orthopedic unmet need and offers new possibilities for clinical translation.”

The study involved six departments at Cedars-Sinai, plus investigators from Hebrew University in Jerusalem; the University of Rochester in Rochester, New York; and the University of California, Davis.

“Our project demonstrates how scientists from diverse disciplines can combine forces to find solutions to today’s medical challenges and help develop treatments for the patients of tomorrow,” said Bruce Gewertz, MD, surgeon-in-chief and chair of the Department of Surgery at Cedars-Sinai.

Reference: Maxim Bez, Dmitriy Sheyn, Wafa Tawackoli, Pablo Avalos, Galina Shapiro, Joseph C. Giaconi, Xiaoyu Da, Shiran Ben David, Jayne Gavrity, Hani A. Awad, Hyun W. Bae, Eric J. Ley, Thomas J. Kremen, Zulma Gazit, Katherine W. Ferrara, Gadi Pelled, Dan Gazit. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Science Translational Medicine, 2017; 9 (390): eaal3128 DOI: 10.1126/scitranslmed.aal3128

lroot on June 2nd, 2017

Liver

Among all the organs in the human body, the liver is something of a superhero. Not only does it defend our bodies against the liquid toxins we regularly ingest, it has the ability to regenerate itself, and, as new research shows, it increases its size by nearly half over the course of a day.

Working in mice, researchers in Switzerland documented this process of regular stretching and shrinking, watching as liver cells swelled in size and contracted up to 40 percent along with the mice’s daily activities. There’s a catch though, a kind of hepatological kryptonite. Their livers only exhibited this ability when the mice followed their normal cycles of eating and resting. They’re nocturnal creatures, and if they began eating during the day when they usually rest, their livers stubbornly refused to grow.

The liver is the only organ known to display such significant cyclical growth, although it does make sense. During the half of the day when we’re not eating, our organs have far less to do. By growing and shrinking to meet demand, our livers are actually trying to save us wasted energy.

The Swiss researchers say that they observed hepatocytes, the main kind of cell in livers, growing during the night when mice were active, something they they attribute largely to an increase in ribosomes, structures in cells that take RNA instructions and use them to produce proteins, among other things. The liver takes material from the food and converts it into useful proteins and other molecules crucial for bodies to function, so possessing more ribosomes means they’re that much better at their jobs. When their daily cycle comes to a close, livers begin breaking down the ribosomes again, like street vendors packing up for the night.

It makes sense that livers would swell when they have to work the hardest. What the researchers found, though, was that it’s not just food intake that tells the liver to ramp up ribosome production — it’s also dependent on what time of day it is. Cells in our livers are also sensitive to circadian rhythms and they found that mouse livers would only begin to grow at night when they ate. Mice fed during the day did not exhibit the same kind of liver growth that their nocturnal counterparts did. The cues that tell the liver to begin preparing for action don’t just come from our food, in other words, they also come from the environment.

Because a bigger liver can work faster and pull out nutrients more efficiently, there’s an obvious advantage to maintaining this kind of cycle. In mice kept nocturnal, there was a noticeable smooth curve of growing and shrinking, and the researchers noticed a 1.6-fold difference in the level of proteins in the liver between the two extremes. In day-fed mice, there was no difference, indicating that their livers weren’t able to produce as much. They published their work Thursday in Cell.

There is evidence that human livers may exhibit the same ability based on a 1986 study that used ultrasound to measure people’s livers over the course of six hours. They found variations of around 20 percent, although they didn’t take any measurements during the night, when our bodily rhythms slow down.

These findings in the liver add to a mounting case for returning to sleep cycles based on environmental cues. Illuminating the night with artificial brilliance has been tied to disrupted sleep cycles in humans, as well as an increased risk for obesity, diabetes, depression and some types of cancer. For millennia, our bodies regulated themselves with the daily rising and setting of the sun, ramping us up when it was light and settling us back down when it got dark. Now, it appears that this extends to our digestive systems as well.

Our livers cleanse toxins from our bodies, produce proteins and chemicals necessary for digestion, recycle old red blood cells and regulate glycogen levels in our bodies. If they aren’t working properly, we can die. While the authors don’t address the implications of their work for humans, their findings could help to explain why it’s unhealthy to go to bed late at night.

Reference: Flore Sinturel, Alan Gerber, Daniel Mauvoisin, Jingkui Wang, David Gatfield, Jeremy J. Stubblefield, Carla B. Green, Frédéric Gachon, Ueli Schibler. Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome Assembly Cycles. Cell, Volume 169, Issue 4, 651 – 663

lroot on June 1st, 2017

Watson Super Computer doctor

Many people know Watson as IBM’s world Jeopardy champion on the television show. Now IBM is turning it’s artificially intelligent supercomputer into a medical genius.

“Watson, the supercomputer, basically went to med school after it won Jeopardy,” MIT’s Andrew McAfee, coauthor of The Second Machine Age, said recently in an interview with Smart Planet. “I’m convinced that if it’s not already the world’s best diagnostician, it will be soon.”

Watson is already capable of storing far more medical information than doctors, and unlike humans, its decisions are all evidence-based and free of cognitive biases and overconfidence. It’s also capable of understanding natural language, generating hypotheses, evaluating the strength of those hypotheses, and learning not just storing data, but finding meaning in it.

As IBM scientists continue to train Watson to apply its vast stores of knowledge to actual medical decision-making, it’s likely just a matter of time before its diagnostic performance surpasses that of even the sharpest doctors.

Back in 2011, McAfee wrote on his blog about why a diagnosis from “Dr. Watson” would be a game changer.

It’s based on all available medical knowledge. Human doctors can’t possibly hold this much information in their heads, or keep up it as it changes over time. Dr. Watson knows it all and never overlooks or forgets anything.

It’s accurate. If Dr. Watson is as good at medical questions as the current Watson is at game show questions, it will be an excellent diagnostician indeed.

It’s consistent. Given the same inputs, Dr. Watson will always output the same diagnosis. Inconsistency is a surprisingly large and common flaw among human medical professionals, even experienced ones. And Dr. Watson is always available and never annoyed, sick, nervous, hung over, upset, in the middle of a divorce, sleep-deprived, and so on.

It has very low marginal cost. It’ll be very expensive to build and train Dr. Watson, but once it’s up and running the cost of doing one more diagnosis with it is essentially zero, unless it orders tests.

It can be offered anywhere in the world. If a person has access to a computer or mobile phone, Dr. Watson is on call for them.

An April study estimated that as many as 1 in 20 U.S. adults are misdiagnosed by their human doctors each year, so it’s an area ripe for improvement and competition.

That’s one reason IBM has been pumping Watson full of medical knowledge a subject area that’s actually significantly more contained than “all the world’s general knowledge,” which is what Watson tried to learn for Jeopardy.

Watson has “read” dozens of textbooks, all of PubMed and Medline (two massive databases of medical journals), and thousands of patient records from Memorial Sloan Kettering. All together, “Watson has analyzed 605,000 pieces of medical evidence, 2 million pages of text, 25,000 training cases and had the assist of 14,700 clinician hours fine-tuning its decision accuracy,” Forbes reported in 2013.

And it’s getting “smarter” every year. So how would Dr. Watson work in practice? Here’s how IBM describes the process:

First, the physician might describe symptoms and other related factors to the system. Watson can then identify the key pieces of information and mine the patient’s data to find relevant facts about family history, current medications and other existing conditions. It combines this information with current findings from tests, and then forms and tests hypotheses by examining a variety of data sources such as treatment guidelines, electronic medical record data and doctors’ and nurses’ notes, as well as peer reviewed research and clinical studies. From here, Watson can provide potential treatment options and its confidence rating for each suggestion.

So far, IBM’s most high-profile AI partnerships are with MD Anderson Cancer Center and WellPoint, where Watson helps the insurer evaluate doctors’ treatment plans.

Watson is not yet able to leverage all the information it has absorbed, so it still has a ways to go before it catches up with our best human diagnosticians, whose versatility and agility is difficult to match. But Watson’s ability to learn, analyze, and apply knowledge suggests that it’s only a matter of time before is surpasses the best human doctors.

“If and when Dr. Watson gets as good at diagnosis as Watson is at Jeopardy I want it as my primary care physician,” McAfee wrote, back in 2011.

That day may come sooner than we imagined.

Tibetan Singing Bowls

A recent study conducted at Baycrest Health Sciences has uncovered a crucial piece into why playing a musical instrument can help older adults retain their listening skills and ward off age-related cognitive declines. This finding could lead to the development of brain rehabilitation interventions through musical training.

The study, published in the Journal of Neuroscience, found that learning to play a sound on a musical instrument alters the brain waves in a way that improves a person’s listening and hearing skills over a short time frame. This change in brain activity demonstrates the brain’s ability to rewire itself and compensate for injuries or diseases that may hamper a person’s capacity to perform tasks.

“Music has been known to have beneficial effects on the brain, but there has been limited understanding into what about music makes a difference,” says Dr. Bernhard Ross, senior scientist at Baycrest’s Rotman Research Institute (RRI) and senior author on the study. “This is the first study demonstrating that learning the fine movement needed to reproduce a sound on an instrument changes the brain’s perception of sound in a way that is not seen when listening to music.”

This finding supports Dr. Ross’ research using musical training to help stroke survivors rehabilitate motor movement in their upper bodies. Baycrest scientists have a history of breakthroughs into how a person’s musical background impacts the listening abilities and cognitive function as they age and they continue to explore how brain changes during aging impact hearing.

The study involved 32 young, healthy adults who had normal hearing and no history of neurological or psychiatric disorders. The brain waves of participants were first recorded while they listened to bell-like sounds from a Tibetan singing bowl (a small bell struck with a wooden mallet to create sounds). After listening to the recording, half of the participants were provided the Tibetan singing bowl and asked to recreate the same sounds and rhythm by striking it and the other half recreated the sound by pressing a key on a computer keypad.

“It has been hypothesized that the act of playing music requires many brain systems to work together, such as the hearing, motor and perception systems,” says Dr. Ross, who is also a medical biophysics professor at the University of Toronto. “This study was the first time we saw direct changes in the brain after one session, demonstrating that the action of creating music leads to a strong change in brain activity.”

The study’s next steps involve analyzing recovery between stroke patients with musical training compared to physiotherapy and the impact of musical training on the brains of older adults.

With additional funding, the study could explore developing musical training rehabilitation programs for other conditions that impact motor function, such as traumatic brain injury.

Reference: Bernhard Ross, Masihullah Barat, Takako Fujioka. Sound-making actions lead to immediate plastic changes of neuromagnetic evoked responses and induced beta-band oscillations during perception. The Journal of Neuroscience, 2017; 3613-16 DOI: 10.1523/JNEUROSCI.3613-16.2017

Stem Cells

The emergency call issued by the American Red Cross earlier this year was of a sort all too common: Donations of platelets were needed, and desperately. But a new discovery from the University of Virginia School of Medicine may be the key to stopping shortages of these vital blood-clotting cells.

The UVA researchers have identified a “master switch” that they may be able to manipulate to overcome the obstacles that have prevented doctors from producing platelets in large quantities outside the body. “The platelet supply is limited and the demand is growing,” said researcher Adam Goldfarb, MD, of UVA’s Department of Pathology. “The quantities we can produce outside the body are very, very small, and the inability to scale up right now is a major roadblock. We think that our understanding of this pathway is actually a critical step toward fixing that problem.”

Scientists also may be able to use this master switch to battle neonatal thrombocytopenia, a condition that complicates the care of babies who are already at great risk. “It turns out in premature infants and newborns that [the platelet] reserve is compromised. They are less capable of responding to distress and the demand for increased platelet production,” Goldfarb said. “A goodly percentage of those babies, these tiny little babies, require platelet transfusions to keep their platelets up.”

The switch discovered by Goldfarb’s team controls whether the bone marrow produces cells called megakaryocytes of the type seen in adults or of the sort found in infants. This is important because the adult and infantile versions have very different specialties: Adult megakaryocytes are great at making platelets. Lots and lots of them. Infantile megakaryocytes, on the other hand, are much smaller cells, and they concentrate on dividing to produce more megakaryocytes.

The ability to toggle between the two could be a huge asset for doctors. Now, doctors cannot produce large quantities of platelets in the lab and instead must rely on platelet donations for patients. The new finding, however, may help change that. “It’s thought that in our bodies every single megakaryocyte produces like a thousand platelets, and when you do it in culture [outside the body] it’s like 10,” he said. “We think the pathway we’re studying enhances the efficiency of platelet release, and this pathway, we think, could be manipulated in both directions: to suppress the pathway to promote the growth [of megakaryocytes] and then to activate the pathway at some point to enhance the efficiency of platelet release.”

For example, babies might be given a drug that would prompt their bodies to make more platelets. Researcher Kamal Elagib, MBBS, PhD, noted that the research team already has identified compounds that can flip the switch in the lab, but that those compounds likely aren’t the best option for treatment: “Those inhibitors have multiple effects, so there would be side effects,” he said.

The researchers, however, have already identified other drugs that look much more promising. “Our future efforts that Kamal is working on now are to identify better, cleaner, more effective approaches at flipping this switch,” Goldfarb said. “Understanding this process could really enhance the future approaches towards treating patients with low platelet counts.”

Reference: Kamaleldin E. Elagib, Chih-Huan Lu, Goar Mosoyan, Shadi Khalil, Ewelina Zasadzi?ska, Daniel R. Foltz, Peter Balogh, Alejandro A. Gru, Deborah A. Fuchs, Lisa M. Rimsza, Els Verhoeyen, Miriam Sansó, Robert P. Fisher, Camelia Iancu-Rubin, Adam N. Goldfarb. Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition. Journal of Clinical Investigation, 2017; DOI: 10.1172/JCI88936

lroot on April 28th, 2017

heart

Generating mature and viable heart muscle cells from human or other animal stem cells has proven difficult for biologists. Now, Johns Hopkins researchers report success in creating them in the laboratory by implanting stem cells taken from a healthy adult or one with a type of heart disease into newborn rat hearts.

The researchers say the host animal hearts provide the biological signals and chemistry needed by the implanted immature heart muscle cells to progress and overcome the developmental blockade that traditionally stops their growth in lab culture dishes or flasks.

In a summary of the work published Jan. 10 in Cell Reports, the researchers say their method should help advance studies of how heart disease develops, along with the development of new diagnostic tools and stem cell treatments.

“Our concept of using a live animal host to enable maturation of cardiomyocytes can be expanded to other areas of stem cell research and really opens up a new avenue to getting stem cells to mature,” says Chulan Kwon, Ph.D., associate professor of medicine and member of the Johns Hopkins University School of Medicine’s Institute for Cell Engineering, who led the study.

According to Kwon, cell biologists have been historically unable to induce heart muscle cells to get past the point in development characteristic of newborns, even when they let them mature in dishes for a year.

Those neonatal heart cells, Kwon explains, are smaller and rounder than mature adult heart cells and generate very low pumping force. As a result, he adds, they aren’t the best model for heart muscle diseases, nor do they accurately mimic the biology and chemistry of adult heart tissue.

Kwon’s group recently showed that cells kept and grown in lab dishes weren’t turning on the proper genes needed to let the cells transition to maturity, a phenomenon they attributed to the artificial conditions of growing cells in a dish. But they also found that those genes were similar to those activated, or turned on, in the hearts of newborn rats.

In their initial experiments designed to overcome the developmental roadblock, the researchers first created a cell line of immature heart cells taken from mouse embryonic stem cells. They next tagged these cells with a fluorescent protein and injected about 200,000 of the cells into the ventricle or lower heart chamber of newborn nude rats — rats with deficient immune systems that wouldn’t attack and reject the newly introduced cells.

After about a week, Kwon reports, the fluorescent cells were still rounded and immature-looking. After a month, however, the cells looked like adult heart muscle cells — elongated with striped patterns.

When the researchers compared 312 genes in the individual mouse cells grown in the rat hearts to the genes found in both immature heart cells and adult heart muscle cells, they found the cells grown in the rat hearts had more in common with genetics of adult heart muscle cells.

The investigators confirmed that the new heart-grown cells could contract or beat like normal adult heart muscle cells using a type of optical microscopy.

In the next set of proof-of-concept experiments, Kwon’s team worked with human adult skin cells from a healthy human donor that were chemically converted back into a stem cell-like state known as induced pluripotent stem cells. A month after these cells were implanted into newborn rat hearts, the healthy human donor cells appeared rod-shaped and mature.

Kwon cautions that clinical use of these lab-grown cells is years away. But, he says, “The hope is that our work advances precision medicine by giving us the ability to make adult cardiomyocytes from any patient’s own stem cells.” Having that capability, he says, means having a way to test each patient for old and new drug sensitivities and value, and to have a scalable process to create large cell sources for heart regeneration.”

Reference: 1.Gun-Sik Cho, Dong I. Lee, Emmanouil Tampakakis, Sean Murphy, Peter Andersen, Hideki Uosaki, Stephen Chelko, Khalid Chakir, Ingie Hong, Kinya Seo, Huei-Sheng Vincent Chen, Xiongwen Chen, Cristina Basso, Steven R. Houser, Gordon F. Tomaselli, Brian O’Rourke, Daniel P. Judge, David A. Kass, Chulan Kwon. Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. Cell Reports, 2017; 18 (2): 571 DOI: 10.1016/j.celrep.2016.12.040