The Forest Whispers My Name III » stem

Scientists create stable, self-renewing neural stem cell

pmb — Tue, 26 Apr 2011 09:55:58 +0000

In a paper published in the April 25 early online edition of the Proceedings of the National Academy of Sciences, researchers at the University of California, San Diego School of Medicine, the Gladstone Institutes in San Francisco and colleagues report a game-changing advance in stem cell science: the creation of long-term, self-renewing, primitive neural precursor cells from human embryonic stem cells (hESCs) that can be directed to become many types of neuron without increased risk of tumor formation.

“It’s a big step forward,” said Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at Shiley Eye Center and director of the Institute for Genomic Medicine, both at UC San Diego. “It means we can generate stable, renewable neural stem cells or downstream products quickly, in great quantities and in a clinical grade – millions in less than a week – that can be used for clinical trials and, eventually, for clinical treatments. Until now, that has not been possible.”

Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors.

To produce the neural stem cells, Zhang, with co-senior author Sheng Ding, PhD, a former professor of chemistry at The Scripps Research Institute and now at the Gladstone Institutes, and colleagues added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process.

“And because it doesn’t use any gene transfer technologies or exogenous cell products, there’s minimal risk of introducing mutations or outside contamination,” Zhang said. Assays of these neural precursor cells found no evidence of tumor formation when introduced into laboratory mice.

By adding other chemicals, the scientists are able to then direct the precursor cells to differentiate into different types of mature neurons, “which means you can explore potential clinical applications for a wide range of neurodegenerative diseases,” said Zhang. “You can generate neurons for specific conditions like amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), Parkinson’s disease or, in the case of my particular research area, eye-specific neurons that are lost in macular degeneration, retinitis pigmentosa or glaucoma.”

The new process promises to have broad applications in stem cell research. The same method can be used to push induce pluripotent stem cells (stem cells artificially derived from adult, differentiated mature cells) to become neural stem cells, Zhang said. “And in principle, by altering the combination of small molecules, you may be able to create other types of stem cells capable of becoming heart, pancreas, or muscle cells, to name a few.”

The next step, according to Zhang, is to use these stem cells to treat different types of neurodegenerative diseases, such as macular degeneration or glaucoma in animal models.

Funding for this research came, in part, from grants from National Institutes of Health Director’s Transformative R01 Program, the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Institute of Mental Health, the California Institute for Regenerative Medicine, a VA Merit Award, the Macula Vision Research Foundation, Research to Prevent Blindness, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the Richard and Carol Hertzberg Fund.

Co-authors of the study include Wenlin Li, Yu Zhang, Wanguo Wei, Rajesh Ambasudhan, Tongxiang Lin, Janghwan Kim, Department of Chemistry, The Scripps Research Institute; Woong Sun, Xiaolei Wang, UCSD Institute for Genomic Medicine and Shiley Eye Center, Department of Anatomy, Korea University College of Medicine, Seoul, Korea; Peng Xia, Maria Talantova, Stuart A. Lipton, Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute; Woon Ryoung Kim, Department of Anatomy, Korea University College of Medicine, Seoul, Korea.

Stem Cell Transplant May Help Aggressive MS: Study

pmb — Mon, 21 Mar 2011 21:59:36 +0000

Stem cell transplants may hold some hope for patients with rapidly progressing multiple sclerosis, the authors of a long-term study report.

The controversial treatment, known as hematopoietic stem cell transplantation (HSCT), involves ablating, or removing, the patients’ immune and other blood cells, then replacing it with new bone marrow stem cells from the same patient.

The idea is to “reset the thermostat and start fresh,” said Dr. Aaron Miller, chief medical officer for the National Multiple Sclerosis Society and a professor of neurology at Mount Sinai School of Medicine in New York City.

But Miller, who was not involved in the study, doubts the procedure will become a viable option for patients with aggressive multiple sclerosis.

“This is a very heroic form of therapy for multiple sclerosis [MS], which is unlikely, in my view, ever to have a major impact on the field,” added Miller. “It’s a substantially risky therapy — the mortality rates have been in the 2-3 percent range . . . and it’s hugely expensive.”

MS is a disease of the nervous system. There is no known cause or cure, and in severe cases patients may be unable to write, speak or walk.

This study, published in the March 22 issue of Neurology, was begun 15 years ago. Back then, “perhaps we didn’t have other good alternatives for aggressive disease,” he said. “I think we now have better and safer alternatives.”

Those alternatives include the biologic therapies Tysabri (natalizumab) and Gilenya (fingolimod), approved in 2006 and 2010, respectively. But Miller emphasized these can only be considered “potentially” more effective than HSCT because the two have never been tested head-to-head.

The trial organizers reported earlier that 80 percent of patients receiving HSCT treatment had stabilized disease after five years. They also noted positive brain changes on an MRI.

Now, after 15 years, the authors report that overall 25 percent of the 35 initial patients are stabilized. The success rate was better — 44 percent — for those with active brain lesions, signaling aggressive disease, they found.

Many had a lessening of their disability, and fewer and smaller lesions in the brain.

But two participants, or 6 percent, died of complications from the transplant.

Research on this aggressive therapy is continuing, say the authors, from Aristotle University of Thessaloniki Medical School in Greece.

But more information might be hard to come by because the treatment’s high mortality rate makes it difficult to recruit patients.

Still, they said, HSCT might be a “salvage” therapy for hard-to-treat MS.

“It’s a possible treatment strategy, but it remains to be seen how much of a treatment option it is,” said Dr. Mark Keegan, associate professor of neurology at the Mayo Clinic in Rochester, Minn.

“We do need ways to treat people with aggressive MS,” he added.

Multiple sclerosis ‘could be reversed by activating stem cells in brain’

pmb — Mon, 06 Dec 2010 08:16:05 +0000

A new study has suggested that the damage caused by multiple sclerosis could be reversed by activating stem cells that can repair injury in the central nervous system.
Researchers from the Universities of Cambridge and Edinburgh have identified a mechanism essential for regenerating insulating layers- known as myelin sheaths-that protect nerve fibres in the brain.

In multiple sclerosis, loss of myelin leads to the nerve fibres in the brain becoming damaged. These nerve fibres are important as they send messages to other parts of the body.

The scientists believe that this research will help in identifying drugs to encourage myelin repair in multiple sclerosis patients.

Robin Franklin, Director of the MS Society”s Cambridge Centre for Myelin Repair at the University of Cambridge, said: “Therapies that repair damage are the missing link in treating multiple sclerosis. In this study we have identified a means by which the brain”s own stem cells can be encouraged to undertake this repair, opening up the possibility of a new regenerative medicine for this devastating disease.”

Charles ffrench-Constant, of the University of Edinburgh”s MS Society Centre for Multiple Sclerosis Research, said: “The aim of our research is to slow the progression of multiple sclerosis with the eventual aim of stopping and reversing it. This discovery is very exciting as it could potentially pave the way to find drugs that could help repair damage caused to the important layers that protect nerve cells in the brain.”

The study was published in Nature Neuroscience.

Advanced nerve cell system could help cure MS, related diseases

pmb — Wed, 24 Jun 2009 11:56:52 +0000

Multiple sclerosis, diabetic neuropathy, and other conditions caused by a loss of myelin insulation around nerves can be debilitating and even deadly, but adequate treatments do not yet exist. That’s in large part because of deficiencies in model research systems. In an upcoming issue of the journal Biomaterials, a UCF team addresses this problem with a report on the first lab-grown motor nerves that are insulated and organized the same way they are in the body.

The group’s model system, along with further advances now within reach, could dramatically improve understanding of the causes of myelin-related conditions, and enable discovery and testing of new drug therapies.

Nerve malfunctions, or neuropathies, involve a breakdown in the way the brain sends and receives electric signals along nerve cells. In mammals, these signals are able to travel long distances because of breaks in their myelin insulation called nodes of Ranvier, each of which chemically boosts the signal, allowing it to travel to the next node. “They’re like power station relays,” says James Hickman, a bioengineer at UCF who led the new research, which achieved the first successful nodes of Ranvier formation ever on motor nerves in a lab culture, among other advances.

Multiple sclerosis (MS), diabetic neuropathy, Guillain-Barré syndrome, and other demyelinating conditions are caused when nerve signals can’t travel their normal path from node to node due to myelin breakdown. Within the brain and spinal cord, where the damage from MS occurs, cells called oligodendrocytes surround the nerves and produce this critical myelin. In the peripheral nervous system, where the problems associated with diabetic neuropathy originate, Schwann cells perform this function.

Due to the famous complexity of the nervous system, studying demyelinating neuropathies has proven exceedingly challenging. “People have basically been stuck doing work in animal models, and they don’t work very well,” says Hickman.

Researchers have long recognized the need for lab-grown motor nerve cells that myelinate and form nodes of Ranvier so that, under controlled laboratory conditions, they can zero in on the causes of and solutions for demyelination. Researchers have achieved Myelination and nodes of Ranvier formation with sensory neurons, but accomplishing the same task with the motor nerves that play more critical roles in some diseases has remained an elusive goal.

Working with Hickman, UCF graduate student John Rumsey was able to accomplish this very feat, though, for the first time. “It was exciting because it was totally unexpected,” says Hickman. The key to their surprising successes is one that other researchers in the field may find surprising, and one that makes their new model system better suited to advancing neuropathy research than anything ever before available.

“It was such a long shot I didn’t believe the results at first,” says James Hickman, leader of the team that developed the new model, “It took two months before I was convinced we had what he had.”

Accomplishing the Complex by Keeping It Simple

Nerve cells in the body grow in two strikingly different environments. In the relatively open peripheral nervous system, cells are exposed to blood and other fluids that contain high protein concentrations and copious other constituents in variable concentrations. In the isolated central nervous system the spinal cord and brain are instead surrounded by cerebrospinal fluid that is nearly sterile, with only a trace of protein.

Especially during initial experiments, researchers typically grow cell cultures in serum isolated from cow or human blood, which effectively promotes growth. But serum also complicates studies by making it difficult to discern the relative impacts of different chemical components. Once growth in serum is accomplished, researchers will often attempt culturing in a serum-free medium, especially for drug discovery work where serum’s components make it difficult to isolate the effects of a drug.

Past research aimed at getting Schwann cells to myelinate motor nerves, or motoneurons, had followed this pattern, but the Hickman group began serum-free. They had already developed techniques for growing various nervous system cells in serum-free media, including motoneurons, so they decided to attempt myelination using the growth medium they have spent years tweaking.

Hickman hypothesizes that while serum contains components that promote cell growth it may also contain some that inhibit growth. Therefore, starting with a serum-free medium, rather than ending there, may well have led to the team’s success.

What’s Next: Drug Discovery Potential

Among numerous goals, the Hickman team plans to use their new model system to explore the origins of diabetic neuropathy, a condition that can cause a range of complications from digestive problems to pain in the limbs.

Currently researchers have incomplete understanding of even the basics of how demyelination occurs. So, one line of experiments will be to treat cultured motoneuron systems with factors found in high concentrations in diabetics, such as fatty acids or cholesterol. This will allow them to identify what causes myelin to degrade, which could in turn help them identify targets for new drug therapies that could also be tested using the model. Other planned experiments will focus on how electrical signals travel through myelinated and unmyelinated nerves to reveal how nerves malfunction.

“Being able to study these fully developed structures means we can really start looking at these things in a way that just wasn’t possible before,” says Hickman.

Though the myelination work has involved embryonic rat cells, the Hickman team was also the first to culture adult motoneurons and hopes to eventually extend myelination work to those as well. Such an advance would, for instance, offer a more realistic model for spinal cord injury research. Effective treatment of spinal injuries would be dependant on remyelination of adult motoneurons, including nodes of Ranvier formation. If that can be achieved in the lab, it will be a sign of hope that treatments could be developed to accomplish the same in patients.

Another major goal for the Hickman group will be to induce myelination by the oligodendrocytes that insulate the central nervous system motoneurons involved in multiple sclerosis, a goal preliminary experiments suggest may be achievable.

Even without that advance, the Schwann cell myelination model could reveal new drug treatment possibilities for multiple sclerosis based on improved understanding of demyelination. For the roughly 400,000 Americans and countless others around the globe suffering from this and other related diseases with limited treatment options, all these possibilities are sure to be welcome news.

Source: University of Central Florida

Current Mood: cool

Recipe created for turning skin cells into stem cell lookalikes

pmb — Sun, 31 May 2009 03:04:35 +0000

Continuing advances in a fast-growing field, biologists reported a purely-chemical recipe for growing normal skin cells into human embryonic stem cell lookalikes.

Called “induced pluripotent” stem cells, researchers hope to see whether these lookalikes can grow into all organ tissues like embryonic stem cells, making them candidates for transplant medicine treatments in the future.

Reported in the journal Cell Stem Cell, the team headed by Kwang-Soo Kim of Harvard Medical School describes a method for treating skin cells with proteins produced by four cancer genes that trigger the transformation into induced pluripotent cells, a change first demonstrated in 2006.

“This is the first safe method for producing (induced pluripotent cells),” says study co-author Robert Lanza of Advanced Cell Technology in Worcester, Mass. Previous methods involved inserting the cancer genes into the skin cells, and then removing them by various methods. In the study, the researchers bound their proteins to cell-penetrating molecules, treated skin cells with them for 16 hours, and then grew them for six days over a number of cycles. The process produced two colonies, or lines, of induced pluripotent stem cells that continue to grow today, and contain the same gene markers as embryonic stem cells.

“The work represents another important milestone, however, challenges remain,” says University of Wisconsin stem cell biologist James Thomson., by e-mail. “The most important criteria for choosing a particular reprogramming approach will be whether one can derive an (induced pluripotent stem) cell line from an easily obtained clinical sample consistently, and whether the resulting (induced pluripotent) cell line has a normal genetic and epigenetic (gene activation) status. It is not yet clear what approach, or combination of approaches, will most consistently meet these criteria.”

One limitation of the study’s protein approach is its low efficiency, about 100 times less likely to produce cell lines than the already very-inefficient genetic engineering approaches. Marius Wernig of Stanford University, for example, says, “it is also clear that the method described is far from being robust and there is a lot more to do until this approach will become really applicable in a reproducible manner.”

However Lanza says that purified forms of the proteins applied to skin cells will raise the processes’ efficiency. “We are moving ahead to see how these cells differentiate into (organ) tissues,” Lanza says. “So far they are doing so beautifully.”

Current Mood: bouncy