First Stem Cell Study of Bipolar Disorder Yields Promising Results

Stem cell model shows nerve cells develop, behave and respond to lithium differently – opening doors to potential new treatments

Tuesday, 25 March 2014

What makes a person bipolar, prone to manic highs and deep, depressed lows? Why does bipolar disorder run so strongly in families, even though no single gene is to blame? And why is it so hard to find new treatments for a condition that affects 200 million people worldwide?

New stem cell research published by scientists from the University of Michigan Medical School, and fuelled by the Heinz C. Prechter Bipolar Research Fund, may help scientists find answers to these questions.

These cells, grown from skin cells taken from

people with bipolar disorder, arose from stem

cells and were coaxed to become neural

progenitor cells -- the kind that can become any

sort of nervous system cell. The research showed

differences in cell behaviour compared with cells

grown from people without bipolar disorder.

Credit: University of Michigan Pluripotent Stem
Cell Research Lab. 

The team used skin from people with bipolar disorder to derive the first-ever stem cell lines specific to the condition. In a new paper in Translational Psychiatry, they report how they transformed the stem cells into neurons, similar to those found in the brain – and compared them to cells derived from people without bipolar disorder.

The comparison revealed very specific differences in how these neurons behave and communicate with each other, and identified striking differences in how the neurons respond to lithium, the most common treatment for bipolar disorder.

It's the first time scientists have directly measured differences in brain cell formation and function between people with bipolar disorder and those without.

The researchers are from the Medical School's Department of Cell & Developmental Biology and Department of Psychiatry, and U-M's Depression Center.

Stem cells as a window on bipolar disorder

The team used a type of stem cell called induced pluripotent stem cells, or iPSCs. By taking small samples of skin cells and exposing them to carefully controlled conditions, the team coaxed them to turn into stem cells that held the potential to become any type of cell. With further coaxing, the cells became neurons.

"This gives us a model that we can use to examine how cells behave as they develop into neurons. Already, we see that cells from people with bipolar disorder are different in how often they express certain genes, how they differentiate into neurons, how they communicate, and how they respond to lithium," says Sue O'Shea, Ph.D., the experienced U-M stem cell specialist who co-led the work.

"We're very excited about these findings. But we're only just beginning to understand what we can do with these cells to help answer the many unanswered questions in bipolar disorder's origins and treatment," says Melvin McInnis, M.D., principal investigator of the Prechter Bipolar Research Fund and its programs.

"For instance, we can now envision being able to test new drug candidates in these cells, to screen possible medications proactively instead of having to discover them fortuitously."

The research was supported by donations from the Heinz C. Prechter Bipolar Research Fund, the Steven M. Schwartzberg Memorial Fund, and the Joshua Judson Stern Foundation. The A. Alfred Taubman Medical Research Institute at the U-M Medical School also supported the work, which was reviewed and approved by the U-M Human Pluripotent Stem Cell Research Oversight committee and Institutional Review Board.

O'Shea, a professor in the Department of Cell & Developmental Biology and director of the U-M Pluripotent Stem Cell Research Lab, and McInnis, the Upjohn Woodworth Professor of Bipolar Disorder and Depression in the Department of Psychiatry, are co-senior authors of the new paper.

McInnis, who sees first-hand the impact that bipolar disorder has on patients and the frustration they and their families feel about the lack of treatment options, says the new research could take treatment of bipolar disorder into the era of personalized medicine.

Not only could stem cell research help find new treatments, it may also lead to a way to target treatment to each patient based on their specific profile – and avoid the trial-and-error approach to treatment that leaves many patients with uncontrolled symptoms.

More about the findings:

The skin samples were used to derive the 42 iPSC lines. When the team measured gene expression first in the stem cells, and then re-evaluated the cells once they had become neurons, very specific differences emerged between the cells derived from bipolar disorder patients and those without the condition.

These colourful neurons, seen forming connections

to one another across synapses, were grown from

induced pluripotent stem cells -- ones that were

derived from skin cells taken from people with

bipolar disorder. New research shows they act, and

react to the bipolar drug lithium, differently from

neurons derived from people without bipolar

disorder. Credit: University of Michigan Pluripotent 
Stem Cell Research Lab.

Specifically, the bipolar neurons expressed more genes for membrane receptors and ion channels than non-bipolar cells, particularly those receptors and channels involved in the sending and receiving of calcium signals between cells.

Calcium signals are already known to be crucial to neuron development and function. So, the new findings support the idea that genetic differences expressed early during brain development may have a lot to do with the development of bipolar disorder symptoms – and other mental health conditions that arise later in life, especially in the teen and young adult years.

Meanwhile, the cells' signalling patterns changed in different ways when the researchers introduced lithium, which many bipolar patients take to regulate their moods, but which causes side effects. In general, lithium alters the way calcium signals are sent and received – and the new cell lines will make it possible to study this effect specifically in bipolar disorder-specific cells.

Like misdirected letters and packages at the post office, the neurons made from bipolar disorder patients also differed in how they were 'addressed' during development for delivery to certain areas of the brain. This may have an impact on brain development, too.

The researchers also found differences in microRNA expression in bipolar cells – tiny fragments of RNA that play key roles in the "reading" of genes. This supports the emerging concept that bipolar disorder arises from a combination of genetic vulnerabilities.

The researchers are already developing stem cell lines from other trial participants with bipolar disorder, though it takes months to derive each line and obtain mature neurons that can be studied. They will share their cell lines with other researchers via the Prechter Repository at U-M. They also hope to develop a way to use the cells to screen drugs rapidly, called an assay.

Source: University of Michigan Health System 

Contact: Kara Gavin

Reference:

Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients

H M Chen, C J DeLong, M Bame, I Rajapakse, T J Herron, M G McInnis and K S O’Shea

Translational Psychiatry (2014) 4, e375; doi:10.1038/tp.2014.12

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Replacing Insulin Through Stem Cell-derived Pancreatic Cells under the Skin

A newly created method of placing stem cell-derived pancreatic cells in capsules under the skin to replace insulin is tested in diabetic disease models

Tuesday, 25 March 2014

Microscopic view of Islet of Langerhans in the

pancreas. Beta cells in the Islets are responsible

for producing insulin. Credit: Courtesy of Sanford-

Burnham Medical Research Institute. 

Sanford-Burnham Medical Research Institute (Sanford-Burnham) and UC San Diego School of Medicine scientists have shown that by encapsulating immature pancreatic cells derived from human embryonic stem cells (hESC), and implanting them under the skin in animal models of diabetes, sufficient insulin is produced to maintain glucose levels without unwanted potential trade-offs of the technology. The research suggests that encapsulated hESC-derived insulin-producing cells hold great promise as an effective and safe cell-replacement therapy for insulin-dependent diabetes.

"Our study critically evaluates some of the potential pitfalls of using stem cells to treat insulin-dependent diabetes," said Pamela Itkin-Ansari, Ph.D., adjunct assistant professor in the Development, Aging, and Regenerative Program at Sanford-Burnham, with a joint appointment at UC San Diego.

"We have shown that encapsulated hESC-derived pancreatic cells are able to produce insulin in response to elevated glucose without an increase in the mass or their escape from the capsule. These results are important because it means that the encapsulated cells are both fully functional and retrievable," said Itkin-Ansari.

In the study, published online in Stem Cell Research, Itkin-Ansari and her team used bioluminescent imaging to see if encapsulated cells stay in the capsule after implantation.

Previous attempts to replace insulin-producing cells, called beta cells, have met with significant challenges. For example, researchers have tried treating diabetics with mature beta cells, but because mature cells are fragile and scarce, the method is fraught with problems. Moreover, since the cells come from organ donors, they may be recognized as foreign by the recipient's immune system — requiring patients to take immunosuppressive drugs to prevent their immune system from attacking the donor's cells, ultimately leaving patients vulnerable to infections, tumours, and other adverse events.

Encapsulation technology was developed to protect donor cells from exposure to the immune system — and has proven extremely successful in preclinical studies.

Itkin-Ansari and her research team previously made an important contribution to the encapsulation approach by showing that pancreatic islet progenitor cells are an optimal cell type for encapsulation. They found that progenitor cells were more robust than mature beta cells to encapsulate, and while encapsulated, they matured into insulin-producing cells, which secreted insulin only when needed.

"We were thrilled to see that the cells remained fully encapsulated for up to 150 days, the longest period tested,” said Itkin-Ansari.

"Equally important is that we show that the progenitor cells develop glucose responsiveness without a significant change in mass — meaning they don't outgrow their capsule.”

"Next steps for the development of the approach will be to figure out the size of the capsule required to house the number of progenitor beta cells needed to respond to glucose in humans. And of course we want to learn how long a capsule will function once implanted. Given these goals and continued successful results, I expect to see the technology become a treatment option for patients with insulin-dependent diabetes," said Itkin-Ansari.

Source: Sanford-Burnham Medical Research Institute 

Contact: Susan Gammon, Ph.D.

Reference:

Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape

Kaitlyn Kirk, Ergeng Hao, Reyhaneh Lahmy, Pamela Itkin-Ansari

Stem Cell Research, online 24 March 2014, http://dx.doi.org/10.1016/j.scr.2014.03.003

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A New Way to Make Muscle Cells from Human Stem Cells

A New Way to Make Muscle Cells from Human Stem Cells

Friday, 21 March 2014

Muscle cells are stained green in this micrograph

of cells grown from embryonic stem cells in the

lab of Masatoshi Suzuki at the University of

Wisconsin–Madison. Cell nuclei are stained blue;

the muscle fibres contain multiple nuclei. Nuclei

outside the green fibres are from non-muscle cells.

Suzuki has developed a new method of growing

stem cells into muscle cells that could be more

suitable for treating disease. Suzuki hopes to

experiment next with animals that model muscular

dystrophy and amyotrophic lateral sclerosis.

Credit: Masatoshi Suzuki. 

As stem cells continue their gradual transition from the lab to the clinic, a research group at the University of Wisconsin-Madison has discovered a new way to make large concentrations of skeletal muscle cells and muscle progenitors from human stem cells.

The new method, described in the journal Stem Cells Translational Medicine, could be used to generate large numbers of muscle cells and muscle progenitors directly from human pluripotent stem cells. These stem cells, such as embryonic (ES) or induced pluripotent stem (iPS) cells, can be made into virtually any adult cell in the body.

Adapting a method previously used to make brain cells, Masatoshi Suzuki, an assistant professor of comparative biosciences in the School of Veterinary Medicine, has directed those universal stem cells to become both adult muscle cells and muscle progenitors.

Importantly, the new technique grows the pluripotent stem cells as floating spheres in high concentrations of two growth factors, fibroblast growth factor-2 and epidermal growth factor. These growth factors "urge" the stem cells to become muscle cells.

"Researchers have been looking for an easy way to efficiently differentiate stem cells into muscle cells that would be allowable in the clinic," says Suzuki. The novelty of this technique is that it generates a larger number of muscle stem cells without using genetic modification, which is required by existing methods for making muscle cells.

"Many other protocols have been used to enhance the number of cells that go to a muscle fate," says co-author Jonathan Van Dyke, a post-doctoral fellow in Suzuki's laboratory.

"But what's exciting about the new protocol is that we avoid some techniques that would prohibit clinical applications. We think this new method has great promise for alleviating human suffering."

Last year, Suzuki demonstrated that transplants of another type of human stem cells somewhat improved survival and muscle function in rats that model amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig's disease, ALS destroys nerves and causes a loss of muscle control. The muscle progenitors generated with Suzuki's new method could potentially play a similar role but with enhanced effect.

The new technique can also be used to grow muscle cells from iPS cells from patients with neuromuscular diseases like ALS, spinal muscular atrophy and muscular dystrophy. Thus, the technique could produce adult muscle cells in a dish that carry genetic diseases. These cells could then be used as a tool for studying these diseases and screening potential drug compounds, says Suzuki.

"Our protocol can work in multiple ways and so we hope to provide a resource for people who are exploring specific neuromuscular diseases in the laboratory."

The new protocol incorporates a number of advantages. First, the cells are grown in defined supplements without animal products such as bovine serum, enhancing the clinical safety for the muscle stem cells. Second, when grown as spheres, the cells grow faster than with previous techniques. Third, 40 to 60 percent of the cells grown using the process are either muscle cells or muscle progenitors, a high proportion compared to traditional non-genetic techniques of generating muscle cells from human ES and iPS cells.

Suzuki and his group hope that by further manipulating the chemical environment of the spheres of stem cells, they may increase that number, further easing the path toward human treatment.

Source: University of Wisconsin-Madison 

Contact: Masatoshi Suzuki

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Proteins That Control Energy Use Necessary to Form Stem Cells

Findings advance efforts to reprogram mature cells for organ repair

Thursday, 20 March 2014

Proteins that regulate energy metabolism are essential for stem cell formation, University of Washington researchers find.

Two proteins that control how cells metabolize glucose play a key role in the formation of human stem cells, UW researchers report.

Pictured from left to right: Hannele Ruohola-

Baker, Julie Mathieu, Amy Ferreccio, Zsuzsa

Agoston, Henrik Sperber, Yalan Xing. Credit: 

Michael McCarthy. 

The findings advance scientists' understanding of stem cell development but also suggest that the proteins, which also play a role in the process that transforms normal cells into cancer stem cells, might also be targets for new cancer therapies, the researchers write.

The findings appear online in the journal Cell Stem Cell. The paper's lead authors are Julie Mathieu, a post-doctoral fellow at the UW and Wenyu Zhou who was a graduate student at UW and is now a postdoctoral scholar at Stanford University, Department of Genetics. Dr. Hannele Ruohola-Baker, UW professor of biochemistry, is the paper's senior author.

In the study, the researchers induced mature human tissue fibroblasts to revert to an earlier stem cell-like state by inserting genes for four proteins, a process called reprogramming.

These reprogrammed cells have the extraordinary ability to develop into any type of cell in the human body, a capacity called pluripotency, and it is hoped that induced-pluripotent stem cells will one day be able to be used to create new tissues and organs to repair and replace those damaged by injury and disease.

Researches have known for some time that during reprogramming, cells must go through a stage in which they shut down metabolic pathway that they use to generate energy from glucose that requires the presence of oxygen in mitochondria, the cell's powerhouse and shift over to another pathway, called the glycolytic pathway, that generates less energy but does not require the presence of oxygen.

This shift may take place because in nature, embryonic and tissue stem cells often must survive in low-oxygen, or hypoxic, conditions.

This transition to a glycolytic state is of particular interest to cancer researchers as well, since as normal cells are transformed into cancer cells, which in many ways resemble stem cells, they, too, go through a glycolytic phase.

In their study, the UW researchers focused on the function of two proteins: hypoxia-induced factor 1α and 2α, or HIF1α and HIF2α. These proteins are transcription factors which mean they affect the regulation of a number of genes, allowing them to dramatically alter a cell's behaviour. The researchers showed through loss-of-function analysis that each protein, HIF1α as well as HIF2α is required for generation of stem cells through reprogramming.

To tease out the impact of HIF1α and 2α on cellular processes in more detail, they stabilized the proteins in an active form and tested what each protein could do alone. They found that when HIF1α was stabilized, the cells went into the glycolytic state and produced more induced pluripotent stem cells than normal.

However, when they just activated HIF2α, they found the cells failed to develop into stem cells.

"This was a big surprise," said Mathieu.

"These proteins are very similar but HIF1α gives you lots of stem cells; HIF2α, none."

If stabilized together, HIF2α won the battle, repressing all stem cell formation.

Further investigation found that HIF2α does indeed promote the shift to glycolysis in an early stage of the cells' reprogramming but if it persists too long has the opposite effect, blocking the progression to the stem cell state.

"HIF2α is like Darth Vader, originally a Jedi who falls to the dark side," said Ruohola-Baker.

"While HIF1α, the good guy is beneficial for reprogramming throughout the process, HIF2α, if not eliminated, turns bad in the middle and represses pluripotency."

HIF2α does this in part by up-regulating the production of another protein, called TRAIL, for TNF-related apoptosis-inducing ligand, that is known to, among other things, cause tumour cells to self-destruct through a process called apoptosis.

Zhou said the findings suggest that there may be other proteins in this protein family that are playing alternating "good guy/bad guy" roles during stem cell development.

"It is very intriguing that HIF2α has the capacity to both promote and repress pluripotency, doing so at different stages in a cellular reprogramming process," she said.

The findings have several implications for stem cell research, says Mathieu: first, they indicate that it may be possible to use HIF1α to greatly increase the number of stem cells in a culture and, second, they suggest it may be possible to induce stem cell formation with HIF proteins alone or in combination with other stimulating factors without inserting genes at the start of the reprogramming process.

But the findings may also have important implications for cancer research Ruohola-Baker added: Both HIF1α and 2α are known to play an important role in the process in which normal cells are transformed into cancer stem cells from which tumors grow, indeed, the presence of activated HIF1α is known to be a marker for aggressive disease.

The finding of this study suggest, Ruohola-Baker said, that it might be possible to interfere with cancer development by either blocking the effect of HIF1α in malignant cells early in the process or stimulating the effect of HIF2 at a later stage.

Source: University of Washington

Contact: Kim Blakeley

Reference:

Hypoxia-Inducible Factors Have Distinct and Stage-Specific Roles during Reprogramming of Human Cells to Pluripotency 

Julie Mathieu, Wenyu Zhou, Yalan Xing, Henrik Sperber, Amy Ferreccio, Zsuzsa Agoston, Kavitha T. Kuppusamy, Randall T. Moon, and Hannele Ruohola-Baker 

Cell Stem Cell, 20 March 2014, 10.1016/j.stem.2014.02.012

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New Stem Cell Line Should Accelerate Embryonic Stem Cell Research

New Stem Cell Line Should Accelerate Embryonic Stem Cell Research

Sunday, 16 March 2014

Researchers at the University of Washington have successfully created a line of human embryonic stem cells that have the ability to develop into a far broader range of tissues than most existing cell lines.

This is Carol Ware, Professor of comparative

medicine, University of Washington. Credit: 
Bryan Donohue. 

"These cells will allow us to gain a much greater understanding of normal embryonic development and have the real potential for use in developing ways to grow new tissues and organs for transplantation," said Carol Ware, a professor in the UW Department of Comparative Medicine and lead author of a paper describing the new cell line appearing in the March 10 issue of the journal Proceedings of the National Academy of Sciences.

The cells, called naïve embryonic stem cells, normally appear at the earliest stages of embryonic development and so retain the ability to differentiate in all the different types of cells of the human body — a capacity called pluripotency.

Researchers had been able to develop naive cells using mouse embryonic stem cells but to create naive human embryonic stem cells has required inserting a set of genes that force the cells to behave like naive cells.

While these "transgenic" cells are valuable research tools, the presence of the artificially introduced genes meant the cells will not develop as normal embryonic cells would nor could they be safely used to create tissues and organs for transplantation.

In an article, Ware and her colleagues from the UW Institute for Stem Cell and Regenerative Medicine describe how they successfully created a line of naive human embryonic stem cells without introducing an artificial set of genes.

They first took embryonic stem cells that are slightly more developed, called primed stem cells, and grew them in a medium that contained factors that switched them back — or "reverse toggled" them — to the naive state.

They then used the reverse toggled cells to develop a culture medium that would keep them in the naive state and create a stable cell line for study and research.

Then having worked out how to maintain the cells in the naive state, Ware and her colleagues harvested naive cells directly from donated human embryos and cultured them in the maintenance medium to see if they could create a stable cell line that had not undergone reverse toggling. After many tries, they succeeded.

While the "reverse toggled" cells are much easier to create and will prove valuable research tools, Ware said, the cells that were directly derived from embryos are the more important advance because they are more likely to behave, grow and develop as embryonic cells do in nature.

The new cell line is called Elf1: "El" for the Ellison Foundation, a major supporter of the lab's work; "f" for female, the sex of the stem cell; and "1" for first.

Source: University of Washington

Contact: Kim Blakeley

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Alzheimer's in a Dish

Stem cells from patients offer model and drug-discovery platform for early-onset form of disease

Wednesday, 05 March 2014

Harvard stem cell scientists have successfully converted skins cells from patients with early-onset Alzheimer's into the types of neurons that are affected by the disease, making it possible for the first time to study this leading form of dementia in living human cells. This may also make it possible to develop therapies far more quickly and accurately than before.

Harvard stem cell scientists Tracy Young-Pearse

(left) and Christina Muratore have converted skins

cells from patients with early-onset Alzheimer's

into the types of neurons affected by the disease,

making it possible to study Alzheimer's in living

human cells. Credit: B. D. Colen/Harvard Staff. 

The research, led by Tracy Young-Pearse, PhD, and published in the journal Human Molecular Genetics, confirmed what had long been observed in mouse models — that the mutations associated with early-onset Alzheimer's disease are directly related to protein cleavage errors that cause a rise in amyloid-beta (Aβ) protein 42, which all people produce but somehow clump together to form plaques in Alzheimer's patients.

"We see this mild increase in Aβ42 in cells from patients with Alzheimer's disease, which seems to be enough to trigger disease processes," said Young-Pearse, a Harvard Stem Cell Institute Affiliated Faculty member at Brigham and Women's Hospital.

"We also see increases of a smaller species of amyloid-beta called Aβ38, which was unexpected as it should not be very aggregation prone. We don't fully understand what it means, but it may combine with other forms of amyloid-beta to stimulate plaque formation."

The patient-derived cells also possessed the second hallmark of Alzheimer's disease, high amounts of the tau protein, or more accurately tau that has been distorted so that the proteins tangle together. The relationship between amyloid-beta and tau is an ongoing chicken-and-egg debate in the Alzheimer's research field, with some researchers associating one or the other, or both, with the cause of the disease. But with the human cells, Young-Pearse and her team, including postdoctoral fellow and study first author Christina Muratore, PhD, could demonstrate that preventing amyloid-beta imbalances reduced levels of distorted tau.

"We used two different antibodies — one of which has been in clinical trials for Alzheimer's — to neutralize the effects of amyloid-beta and showed that you're able to rescue changes in tau," Young-Pearse said.

"Not only is it important experimentally to show that tau elevation is due in some part to altered amyloid-beta accumulation, but it also shows that this is an excellent system for testing different therapeutic options."

Clinical trials to treat neurodegenerative diseases like Alzheimer's have a historically high failure rate, partially because potential drugs are derived from research in non-human models. Young-Pearse and colleagues believe that their strategy of using induced pluripotent stem cells to reprogram patient skin cells into neurons of interest could be used to predict which therapeutics will best help early-onset Alzheimer's patients.

Alzheimer's disease comes in two forms. Both possess the well-known cognitive decline and memory loss, but occur at different times in the patient's life. Early-onset or familial Alzheimer's, which can begin to manifest in a person's 30s, 40s, and 50s, is the less common form. In these cases, genetic mutations have been inherited that lead to the disease. The more common sporadic or late-onset Alzheimer's occurs in a person's 70s, 80s, and 90s, and while certain genes may affect disease prognosis it is not associated with specific mutations.

"In familial Alzheimer's, it's pretty well accepted that a change in amyloid-beta generation sparks something that leads to disease," Young-Pearse said.

"In the sporadic form of the disease, we think the problem isn't necessarily with the generation of amyloid-beta, but possibly with its clearance."

Familial Alzheimer's also affects multiple generations, as the mutations that cause the disease are dominantly inherited and fully penetrant, which means that if a parent has a mutation, they have a 50 percent likelihood of passing the disease on to their children. This early-onset form tends to receive less attention and funding than the late-onset form because it makes up less than 2 percent of all of Alzheimer's cases — still more than half-a-million people.

Young-Pearse is next interested in using the patient-derived cells to figure out why Alzheimer's patients only show disease in areas of the brain, like the hippocampus, which is crucial for memory recall, and not the cerebellum, important for balance and movement. Her lab will examine amyloid-beta and tau in neurons not typically associated with the disease to understand why they remain unaffected. This work may also help identify which form of amyloid-beta is the most toxic.

Other Harvard Stem Cell Institute laboratories are also using patient-derived stem cells to study nervous system disease, like spinal muscular atrophy and amyotrophic lateral sclerosis, more commonly known as Lou Gehrig's disease. A therapeutic screening centre, heading by Lee Rubin, PhD, at the Harvard Department of Stem Cell and Regenerative Biology, is dedicated to using induced pluripotent stem cells to find new drugs for genetic diseases.

"Because of the Harvard Stem Cell Institute, we were able to work with other researchers to make patient cells into any type of neuron," said Young-Pearse, whose lab spent two years fine-tuning protocols with collaborators to generate the neurons needed for her early-onset Alzheimer's study.

"The environment provides a really nice system for testing many kinds of hypotheses."

Source: Harvard University 

Contact: B.D. Colen

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Researchers Find Protein 'Switch' Central to Heart Cell Division

Discovery advances efforts to replace damaged heart muscle

Tuesday, 04 March 2014

In a study that began in a pair of infant siblings with a rare heart defect, Johns Hopkins researchers say they have identified a key molecular switch that regulates heart cell division and normally turns the process off around the time of birth. Their research, they report, could advance efforts to turn the process back on and regenerate heart tissue damaged by heart attacks or disease.

In the heart muscle cell above, the arrows 

show an early sign of replication. Credit: 

Johns Hopkins Medicine. 

"This study offers hope that we can someday find a way to restore the ability of heart cells to divide in response to injury and to help patients recover from many kinds of cardiac dysfunction," says cardiologist Daniel P. Judge, M.D., director of the Johns Hopkins Heart and Vascular Institute's Center for Inherited Heart Diseases.

"Things usually heal up well in many parts of the body through cell division, except in the heart and the brain. Although other work has generated a lot of excitement about the possibility of treatment with stem cells, our research offers an entirely different direction to pursue in finding ways to repair a damaged heart."

Unlike most other cells in the body that regularly die off and regenerate, heart cells rarely divide after birth. When those cells are damaged by heart attack, infection or other means, the injury is irreparable.

Judge's new findings, reported online March 4 in the journal Nature Communications, emerged from insights into a genetic mutation that appears responsible for allowing cells to continue replicating in the heart in very rare cases.

The discovery, Judge says, began with the tale of two infants, siblings born years apart but each diagnosed in their earliest weeks with heart failure. One underwent a heart transplant at three months of age; the other at five months. When pathologists examined their damaged hearts after they were removed, they were intrigued to find that the babies' heart cells continued to divide — a process that wasn't supposed to happen at their ages.

The researchers then hunted for genetic abnormalities that might account for the phenomenon by scanning the small percent of their entire genome responsible for coding proteins. One stood out: ALMS1, in which each of the affected children had two abnormal copies.

The Johns Hopkins researchers also contacted colleagues at The Hospital for Sick Children in Toronto, Canada, who had found the same heart cell proliferation in five of its infant patients, including two sets of siblings. Genetic analysis showed those children had mutations in the same ALMS1 gene, which appears to cause a deficiency in the Alström protein that impairs the ability of heart cells to stop dividing on schedule. The runaway division may be responsible for the devastating heart damage in all of the infants, Judge says.

These mutations, it turned out, were also linked to a known rare recessive disorder called Alström syndrome, a condition associated with obesity, diabetes, blindness, hearing loss and heart disease.

In further experiments, the Johns Hopkins researchers cultured mouse heart cells, and then turned off the ALMS1 gene. Compared to those with normal ALMS1 genes, the number of heart cells in samples without this gene increased by an additional 10 percent. The researchers then contacted colleagues at Jackson Laboratory in Maine who had genetically engineered and bred mice with an ALMS1 mutation. They found that the animals with the mutation had increased proliferation of heart cells after two weeks of age, compared to mice with a normal version of the ALMS1 gene. The cell proliferation did eventually stop in the mice, says Judge, an associate professor at the Johns Hopkins University School of Medicine.

Judge says precise knowledge of the regulatory role played by the ALMS1 mutation should advance the search for ways to help regenerate heart muscle tissue in a controlled fashion. Much work in the field of regeneration has been focused on the use of stem cells, which have the remarkable potential to develop into many different cell types.

Judge cautions that efforts to manipulate ALMS1 to repair damage would be tricky, because uncontrolled proliferation may lead to serious and even lethal complications.

"The children who helped us recognize the importance of this gene were born with a rare condition that leads to heart failure and many other problems, such as diabetes, obesity, blindness and deafness," he says.

"Now we hope to apply these discoveries to help millions of others with heart disease."

Source: Johns Hopkins Medicine 

Contact: Stephanie Desmon

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