022: Stem cell discovery sheds light on placenta development

Life Science Space (June 9, 2008)--Researchers studying embryonic stem cells have explored the first fork in the developmental road, getting a new look at what happens when fertilized eggs differentiate to build either an embryo or a placenta.

By manipulating a specific gene in a mouse blastocyst — the structure that develops from a fertilized egg but is not yet an actual embryo — scientists with the University of Florida's McKnight Brain Institute and the Harvard Stem Cell Institute caused cells destined to build an embryo to instead change direction and build the cell mass that leads to the placenta.

Writing in today's (Monday, June 9) online edition of Nature Genetics, the scientists reveal a cellular signaling mechanism in place at the earliest developmental stage.

Understanding the conditions that cause these cells to go off to different fates may have a bearing on health problems such as ectopic pregnancy, which occurs when the embryo develops outside of the womb in about 1 of 60 pregnancies, or molar pregnancy, which is abnormal tissue growth within the uterus that affects about 1 in every 1,000 pregnancies.

"We originally were exploring factors that might cause embryonic stem cells to become malignant — there is a concern that these cells may cause tumors," said Chi-Wei Lu, Ph.D., an associate neuroscientist at the UF College of Medicine and lead author of the study. "Our experiments led us to discover the signal that initiates the process of embryonic tissue differentiation."

By activating a gene called Ras in cells bathed in a very specific culture medium, scientists were able to cause embryonic stem cells — which originate from the inner cell mass of the blastocyst — to become more like the trophoblastic stem cells that give rise to the placenta from the outer portion of the blastocyst.

Researchers marked these newly minted cells, which they called ES-TS cells, and injected them into mouse embryos. Instead of joining the stem cells that build the embryo, ES-TS cells joined the stem cells that build the placenta. Furthermore, when scientists transferred the engineered mouse embryos to foster mothers, the ES-TS cells went to work exclusively laying the foundation for the placenta.

"This paper highlights the value of embryonic stem cells for understanding early development," said senior author George Q. Daley, M.D., Ph.D., an associate professor of biological chemistry and molecular pharmacology at Harvard Medical School and an associate professor of pediatrics at Children's Hospital Boston. "Embryonic stem cells are more plastic than we had thought. By simply activating the Ras gene, we changed the fate of embryonic stem cells to an entirely unexpected tissue — the placenta. This surprising result has given us an unanticipated insight into early embryo development."

The technique of genetically modifying the cells and growing them in a special medium could be valuable for additional research.

"This is exciting because events that only occur in the early stages of embryonic development are very difficult to study," Lu said. "Just a few models exist, and even in mice, only a limited amount of embryos can be harvested. Now we can culture these cells and have unlimited material to study."

Researchers are only beginning to understand the natural chemical environments that allow for production of different tissues.

"What is nice is that what she has observed in cultures appears to be quite similar to what goes on in early development in animals," said R. Michael Roberts, D.Phil., a professor of molecular biology at the C.S. Bond Life Sciences Center at the University of Missouri-Columbia who did not participate in the research. "Normally, mouse embryonic stem cells aren't easily converted along the pathway to form placental cells, while human embryonic stem cells undergo this transition quite easily. This has always been a puzzle. What she has shown is you can make mouse embryonic stem cells convert unidirectionally to trophoblasts by activating a single gene. This is very helpful for understanding how the placenta develops."

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Source:

University of Florida News: http://news.ufl.edu/2008/06/09/early-devo/

See also:

eurekalert.org: http://www.eurekalert.org/pub_releases/2008-06/uof-scd060908.php

016: Human stem cells used to cure brain disorder

Success in mice could be a breakthrough for disorders such as multiple sclerosis.

Human donor cells (red) spread through the mouse brains and trigger their repair.

(Image Credit:Windrem et al.)

Life Science Space (June 5, 2008)--Human stem cells have been used to correct abnormal brain development in mice with fatal brain disorders, offering hope for treating a range of neurological disorders including some deadly childhood genetic diseases.

Those behind the new treatment hope that human clinical trials could be just a few years away.

The treatment uses human glial progenitor cells — cells that can differentiate into the glial cells that, among other things, make up myelin. Myelin, a protein that insulates the long 'arms' of nerve cells, called axons, helps the conduction of neural signals throughout the nervous system.

A team led by Steven Goldman, at the University of Rochester in New York, took the progenitor cells from white matter in the fetal human brain and injected them into the spinal cords of mutant shiverer mice shortly after their birth.

The mice, which shiver and shake as their name suggests, have severe neurological defects caused by a genetic mutation that stops them producing myelin. Without myelin, neural signals get stuck, causing potentially fatal disease.

“There’s no way we’d be able to conduct a [neural] signal very far if it weren’t for myelin,” Goldman explains. As they develop, shiverer mice become unable to walk forwards, have increasing numbers of seizures, and typically die at just 18–21 weeks of age.

Debilitating diseases

In humans, myelin losses also cause serious diseases. Multiple sclerosis is characterised by myelin loss in some areas of the brain. Some rare childhood diseases are also caused by an inability to produce myelin. One such example is adrenoleukodystrophy, a disease whose profile was raised by the film Lorenzo’s Oil, which tells the story Lorenzo Odone and his family’s battle to find a cure for his condition. Odone died last week, aged 30. “These are awful, awful diseases,” says Goldman.

Goldman has spent four years perfecting a technique to implant human glial progenitor cells into the nervous system of mice. In the experiment, published in the journal Cell Stem Cell (Windrem, M. S. et al. Cell Stem Cell 2, 553-565 (2008), Goldman used five injection sites to allow the human stem cells to penetrate the entire nervous system of the baby mice.

The researchers knew that if the mouse immune system was suppressed, preventing rejection, the mice would have a better chance of survival. So Goldman used mice that were a cross between shiverer mice and mice genetically modified to have their immune system suppressed.

The team treated 26 of these mice with 300,000 human glial progenitor cells each, 29 with a set of control injections, and left 59 untreated. All the mice deteriorated in health in the first 130 days, as is usual for shiverer mice, and by 150 days all of the control and untreated mice had died. But six of the stem-cell-treated mice survived for longer than 130 days, and four of those went on to live for 14 months, at which time they were sacrificed for analysis.

Transformation

The mice that improved showed impressive myelin growth at sites where the new cells had been implanted. “Myelination was much more than anything we’d seen,” says Goldman. The new myelin was also structurally normal.

The mice did better than just survive — as the myelin grew, the mice began to lose signs of being shiverers. They gained normal brain activity, no longer had seizures and lost much of the shakiness. “As they live longer, they slowly but surely get better,” says Goldman.

He thinks that if he can get the mice through the sick stage of their early life, perhaps by giving them anti-convulsants to stop the seizures that cause so much damage, he can improve his rescue rate.The breakthrough is “stunning”, says Ian Duncan, who studies myelin at the University of Wisconsin-Madison. The work will have greatest relevance in treating congenital childhood diseases, he says, although he warns that a practical therapy is still some way away. ”This is a therapy for the future,” he says.

“This is a good proof of principle,” says Goldman. He is optimistic that once his methods meet with the approval of the US Food and Drug Administration, clinical trials in humans may only be a few years away. There is nothing in the biology that needs to be clarified, he says: “The questions become practical.”

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Article linked: http://www.nature.com/news/2008/080604/full/news.2008.875.html

See also @
Stem cells can cure nerve disease
http://ls-space.blogspot.com/2008/06/012-stem-cells-halt-nerve-disease.html

013: Stem cells can cure nerve disease

Life Science Space (June 4, 2008)-- An injection of stem cells has been used to cure mice with a normally fatal nervous system condition.

The therapy which helped repair faulty nerve wiring raises hopes of treatments for children with rare and deadly nervous leukodystrophy disorders.

A UK expert said human treatments were still some way off - but potentially the technique could be used to treat conditions such as multiple sclerosis.

The US study features in the journal Cell: Stem Cell.

The scientists from the University of Rochester Medical Center believe it may be the first time that this type of "shiverer" mouse has been cured.

Its genetic makeup means that its nerve cells do not have enough myelin, a fatty coating which acts like the sheath on an electrical wire.

Without it, nerve signals do not travel properly from cell to cell, causing the trademark shaking and wobbling symptoms, and normally death within four months.

There are dozens of rare human disorders which involve genetic myelin-related faults in the nervous system, most of which are fatal in childhood or young adulthood.

One of the most well-known of these affected Lorenzo Odone, who died last week after decades battling adrenoleukodystrophy.

:: Surviving minority

The US team did not use "true" stem cells, which have the ability to turn into any cell in the body, but precursor stem cells, which can become one of a limited number of cell types.

The green shows neurons in the brain of a mouse that have been remyelinated as a result of stem cell research. (Image Credit: University of Rochester)

The "glial cells" used here can become among other things, oligdendrocytes, the cells which produce the myelin sheath.

The cells were injected in different places in the central nervous system in a bid to see if this could make any difference to the overall symptoms.

For most, it made none, with three-quarters of the 26 mice injected dying around the same time as mice who had received no treatment.

However, for six mice, the difference was stark - in just two months, the cells had spread around, multiplying, and covering nerve cells in the brain and spinal cord, and producing myelin to coat them.

Two of the mice lived longer than usual, but the other four were still alive a year later, free from virtually all symptoms.

:: 'Awful disease'

Professor Steven Goldman, who led the study, said: "We kept expecting them to die, but not only did they not die, they improved day by day.

"It's extremely exciting to think about not only treating but actually curing a disease, particularly an awful disease that affects children.

Professor David Attwell, from University College London, said the study represented an "important proof of principle" that transplantation of these "precursor" cells could help restore myelin not only within people with leukodystrophies, but in theory within those affected by other conditions involving loss of myelin, such as multiple sclerosis, cerebral palsy and spinal cord injury.

However, he said: "The work is still a long way from being applied in humans, and the paper raises several issues which could affect the chances of that happening.

"Only a small fraction of the mice were cured, and it is unclear why." He said that other potential hurdles were whether within humans, defective myelin-producing cells would be as readily replaced by the new transplanted in versions, and whether, as in the mice, the immune system would have to be suppressed prior to treatment.

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Source: http://news.bbc.co.uk/2/hi/health/7435137.stm

See also:

• University of Rochester Medical Center
  
• cell stem cell

011: Stem Cells Work Medical Magic

What stem cell researchers are really studying is how your body was made and how to do it all over again. Embryonic stem cells (or the newer induced-without-embryos variety) can travel down any of the paths below to become skin, heart, brain and other body parts. So-called adult stem cells are stuck in the middle, able to become certain types of cells but not others. In nature, cells don’t travel backward on these developmental paths; stem cell researchers hope to treat disease by getting them to do just that.

>> Paths To A Person:

Image Credit: Forbes.com

>> Stem Cells Work Medical Magic

:: Make Better Antidepressants
Turning on stem cells in the brain could create the next generation of antidepressants. The idea that drugs like Prozac and Zoloft work by boosting the chemical serotonin is so widely known that drug companies use it in their ads. But the drugs' most important function may be to spur the growth of new neurons in the brain--blocking the growth of new brain cells in mice renders Prozac and other antidepressants ineffective. BrainCells Inc. is working on creating mood-elevating drugs that work by causing brain stem cells to grow.

:: Augment Breasts
Cytori Therapeutics, a tiny biotech firm traded on the Nasdaq, has developed a medical device that spots stem cells in fat. The company hopes these might heal lots of different body parts, including the heart. But the first use is breast reconstruction after a partial mastectomy. The idea is that the fat stem cells can be made to regrow tissue in ways fat cells can't. Right now, the device is marketed in Europe. Cytori is conducting clinical trials to test it for breast augmentation that could lead to U.S. approval.

:: Alleviate Down Syndrome
Down syndrome occurs when a person has an extra copy of his or her 21st chromosome. But what exactly goes wrong? A potential culprit is a misfire among a group of signaling proteins that tell stem cells in an embryo how to create a brain. Stanford's Philip Beachy already knew "hedgehog" misfires (the so-called hedgehog genes are essential to embryonic development) could lead to sheep with one eye or with underdeveloped brains. Down syndrome also seems to cause a hedgehog misfire. Fate Therapeutics, which Beachy co-founded, is looking into whether a drug that boosts hedgehog-gene activity could limit the damage from Down Syndrome if it were given to newborns.

:: Treat Cancer
It may be aberrant stem cells in tumors are what make cancer so malignant. In 2003, Stanford oncologist Michael Clarke shocked other scientists by isolating breast cancer stem cells. They formed only 5% of the tumor, but just a couple hundred of them could cause a new tumor in a mouse. Implanting tens of thousands of other breast cancer cells did nothing. The upshot is that the problem with current cancer treatments may be that they kill regular tumor cells but don't kill the stem cells that allow tumors to keep growing. GlaxoSmithKline will pay OncoMed Pharmaceuticals, a company Clarke founded, up to $1.4 billion for developing drugs that kill cancer stem cells.

:: Slow Parkinson's Disease
It is only because of the existence of human embryonic stem cells that researchers can directly study the neurons dying off in Parkinson's. It could be that, in 20 years, almost every medical researcher is going to use embryonic stem cells as basic tools.

Another approach comes from the laboratory of Wisconsin researcher Clive Svendsen. He is creating genetically engineered fetal cells that would act like drug factories in the brain, churning out a growth factor that could prevent brain cells from dying.

:: Make Alzheimer's Drugs
Last year (2005), scientists in the U.S. and Japan discovered a way to create cells that act like embryonic stem cells but without ever using embryos--instead, they use genetically modified viruses to transform adult human cells into embryolike stem cells by activating only four genes.

University of California, San Diego, researcher Lawrence Goldstein is using these so-called "induced pluripotent" stem cells to make neurons that are "genetically identical" to those of Alzheimer's patients. He is collecting 50 skin samples from Alzheimer's patients in order to hunt for new drugs.

:: Create Drugs For Lou Gehrig's Disease
New technologies that create embryo-like stem cells without embryos could be a boon for drug research. Case in point: amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease, which is caused by the sudden death of motor neurons in middle age. First, scientists want to find toxins that kill neurons destined to get ALS, but leave normal neurons alive. Then they hope to find potential drugs that keep the ALS neurons from dying. Such medicines might prove to be effective treatments for the disease.

:: Cure Type 1 Diabetes
Patients with Type 1 diabetes must take four or more shots of insulin a day because their insulin-producing cells have been killed by a haywire immune system.

Novocell, a San Diego biotech, plans to turn embryonic stem cells into these missing insulin producers and inject them into the bodies of diabetics to put their disease into remission. Medical giants J&J and Becton Dickinson are backing the firm. The technique has been successful in mice, but it will take at least three years before Novocell's treatment is ready to be tested in humans.

:: Treat Tay-Sachs Disease
Tay-Sachs disease is a fatal genetic disorder in which a fatty substance builds up in the cells of the brain, eventually killing them.

The problem is that key enzymes that break this fatty substance down are missing. Evan Snyder at the Burnham Institute for Medical Research in La Jolla, Calif., hopes healthy stem cells can treat the disease by replacing these missing enzymes. When his team implanted stem cells into mice with a disease similar to Tay-Sachs, the animals lived at least 70% longer. A human trial could begin next year.

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Source:

http://www.forbes.com/2008/05/28/stem-cells-biz-healthcare-cx_mh_0528medtech_pathschart.html

003: Stemming the tumorous tide

Life Science Space (May 27, 2008)--Cancers grow from stem cells. That discovery should translate into better treatment for tumours of all types.

Image Credit: Wellcome Trust

Stem cells have a controversial reputation, but in truth they are what makes human life possible. Each tissue in the body grows from a particular sort of stem cell. When it divides, one of its daughters remains a stem cell while the other eventually turns into whatever tissue its mother was designed to produce-be it blood, muscle, nerve or whatever. That is how healthy tissues are renewed, and it is now looking likely that it is how unhealthy tissues are renewed, too. Indeed, many researchers think that the underlying cause of cancer is the brakes coming off the regulatory system that stops normal stem cells from reproducing too much. For one of the most important medical discoveries made in recent years is that cancers, too, have stem cells and that these appear to be the source of the rest of the tumour.

This helps to explain why cancers are so hard to deal with. Treatments that kill the bulk of a tumour, but leave the stem cells alive, are only buying time. On the other hand, if all of a tumour’s stem cells could be killed then it would torpedo the old wisdom that no patient is ever cured of cancer, but merely goes into remission. True cures for cancer would be possible.

The cancer-stem-cell theory, though plausible, was based on animal experiments and its relevance to humans was untested. But a series of studies reported recently at a meeting of the American Association for Cancer Research, in San Diego, has changed that. They suggest both that cancer stem cells are very relevant indeed to survival, and that going after them is an excellent idea.

The relevance of cancer stem cells to survival was shown by William Matsui of the Johns Hopkins Sidney Kimmel Cancer Centre in Baltimore. He looked at samples from 268 people with pancreatic cancer and found that the pattern of stem cells in their tumours predicted how long they would live. Those whose tumours had stem cells at their edges (the ‘invasive margin’ in the militaristic jargon of the cancer-warriors) lived on for an average of 14 months. Those who did not lived an average of 18 months. Not a huge difference, but confirmation that cancer stem cells have an impact on the outcome of disease.

Such stem cells, then, are as bad as theory suggests they should be. The question is, can they be eradicated?
Animal tests suggest this is hard. For reasons as yet unknown, stem cells are resistant to standard cancer chem-otherapies. With this in mind, Jeffrey Rosen and his colleagues at Baylor College of Medicine in Houston, Texas, compared samples from breast-cancer patients taken before and after 12 weeks of chemotherapy. They reasoned that if stem cells were resistant in people as well as mice, then the proportion of stem cells within a tumour would increase as more vulnerable cells were killed off in disproportionate numbers.

And that is exactly what happened. Among women treated with old-fashioned chemotherapy, the share of stem cells within their tumours rose from 5% before treatment to 14% afterwards. Dr Rosen, however, went further. In a parallel experiment he looked at a group of women being treated with a new drug called lapatinib. In these people, the proportion of cancer stem cells decreased from 10% before therapy to 7.5% after they were treated.
Lapatinib is a product of the growing field of molecular medicine—the design of drugs to attack specific protein molecules associated with particular diseases. In this case the protein attacked is HER2, a molecule often found on the surface of breast-tumour cells. Ironically, however, it was not lapatinib’s effect on HER2 that made it potent against stem cells. Lapatinib, it turns out, also inhibits the activity of a protein called the epidermal growth factor receptor, which has been found to be important for stem-cell proliferation. When its activity is blocked, a stem cell’s daughters both lack stem-cell qualities and the chain of ‘stem-cellness’ that the system depends on is broken. Hence the proportion of stem cells in the tumour falls.

It is too early to tell if Dr Rosen’s discovery is a life-prolonging one. But Dr Matsui and his colleague, Carol Ann Huff, are thinking along similar lines.

Alongside Dr Matsui’s pancreatic-cancer work, they have been looking at treating multiple myeloma, a type of blood cancer, with a combination of heavy artillery and guided missiles: high-dose cytotoxic chemotherapy to kill the bulk of the cancer cells and antibodies called rituximab. These bind to a protein called CD20 that sits on the surface of cancer stem cells. It was expected to kill them.

Not every experiment works, and this one did not. As expected, patients left with the fewest cancer stem cells after the therapy lived longest. But this was the luck of the draw, for the rituximab failed to kill the cancer stem cells. Indeed, Dr Huff and Dr Matsui could see stem cells coated with the antibodies alive and well in their samples.

The next step, Dr Huff and Dr Matsui agree, is to bring in even more powerful missiles. Another proprietary antibody that binds to CD20, called tositumomab, is radioactively labelled. If this coats the myeloma stem cells in the way that rituximab does, the radiation should kill them.

Researchers at the University of Michigan, where tositumomab was developed, have already begun such an experiment. Andrzej Jakubowiak, who is leading the trial, says four patients have been on the treatment long enough to be evaluated, and three of them have already been taken off other drugs and appear clinically stable—which for advanced myeloma is an unusually good success rate.

The laboratory data also look promising. The radiological bombs seem to be destroying the cancerous stem cells in exactly the predicted manner—although Dr Jakubowiak rightly cautions that too few patients have been treated to allow firm conclusions.

The upshot of all this is that the stem-cell hypothesis of cancer growth looks a good one. It explains a lot of things, and allows biologists to look at tumours in a new way-almost akin to developing organs, albeit ones with no function and growth that is out of control. That insight, and a better understanding of stem-cell biology, may be the chink in cancer’s armour that people have long been searching for. And that is a truly optimistic thought.

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article provided from The Economist: http://www.economist.com/science/displaystory.cfm?story_id=11043891