Advance Understanding of Spinal Muscular Atrophy with Stem Cells

Cedars-Sinai's Regenerative Medicine Institute research sheds new light on cell death in a common, lethal genetic disease in children, suggesting paths for potential treatment
Thursday, 21 June 2012 

Cedars-Sinai's Regenerative Medicine Institute has pioneered research on how motor-neuron cell-death occurs in patients with spinal muscular atrophy, offering an important clue in identifying potential medicines to treat this leading genetic cause of death in infants and toddlers.

The study, published in the June 19 online issue of PLoS ONE, extends the institute's work to employ pluripotent stem cells to find a pharmaceutical treatment for spinal muscular atrophy or SMA, a genetic neuromuscular disease characterized by muscle atrophy and weakness.

"With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process," said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute.

Svendsen and his team have investigated this disease for some time now. In 2009, Nature published a study by Svendsen and his colleagues detailing how skin cells taken from a patient with the disorder were used to generate neurons of the same genetic makeup and characteristics of those affected in the disorder; this created a "disease-in-a-dish" that could serve as a model for discovering new drugs.

As the disease is unique to humans, previous methods to employ this approach had been unreliable in predicting how it occurs in humans. In the research published in PLoS ONE, to the team reproduced this model with skin cells from multiple patients, taking them back in time to a pluripotent stem cell state (iPS cells), and then driving them forward to study the diseased patient-specific motor neurons.

Children born with this disorder have a genetic mutation that doesn't allow their motor neurons to manufacture a critical protein necessary for them to survive. The study found these cells die through apoptosis – the same form of cell death that occurs when the body eliminates old, unnecessary as well as unhealthy cells. As motor neuron cell death progresses, children with the disease experience increasing paralysis and eventually death. There is no effective treatment now for this disease. An estimated one in 35 to one in 60 people are carriers and about in 100,000 new-borns have the condition.

"Now we are taking these motor neurons (from multiple children with the disease and in their pluripotent state) and screening compounds that can rescue these cells and create the protein necessary for them to survive," said Dhruv Sareen, director of Cedars-Sinai's Induced Pluripotent Stem Cell Core Facility and a primary author on the study.

"This study is an important stepping stone to guide us toward the right kinds of compounds that we hope will be effective in the model – and then be reproduced in clinical trials."

Source: Cedars-Sinai Medical Center 

Contact: Nicole White

Reference:

Inhibition of Apoptosis Blocks Human Motor Neuron Cell Death in a Stem Cell Model of Spinal Muscular Atrophy

Dhruv Sareen, Allison D. Ebert, Brittany M. Heins, Jered V. McGivern, Loren Ornelas, Clive N. Svendsen

PLoS ONE, 19 Jun, 2012, 201210.1371/journal.pone

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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Stem Cells Poised to Self-destruct for the Good of the Embryo

Stem Cells Poised to Self-destruct for the Good of the Embryo

Friday, 04 May 2012

Embryonic stem cells — those revered cells that give rise to every cell type in the body — just got another badge of honour. If they suffer damage that makes them a threat to the developing embryo, they swiftly fall on their swords for the greater good, according to a study published online May 3, 2012 in the journal Molecular Cell.

This is an image depicting active Bax 

(red) located at Golgi of human embryonic 

stem cells. Nuclei are stained in blue.

Credit: Deshmukh Lab, UNC-Chapel Hill. 

The finding offers a new glimpse into the private lives of stem cells that could help scientists use them to grow new neurons or other cells to replace those that have been lost in patients with Parkinson's and other diseases.

"Despite the huge potential of stem cells for therapeutic use, very few people have actually investigated their basic biology," said study senior researcher Mohanish Deshmukh, PhD, professor of cell and developmental biology at the University of North Carolina at Chapel Hill.

"These results could have significant implications from a therapeutic perspective."

Of all the important things our bodies' cells do, staying alive is clearly key. But a cell's ability to die when something goes wrong is equally critical. For example, a faulty self-destruct button is one factor that allows cancer cells to proliferate unchecked and cause tumours.

Deshmukh and his colleagues discovered stem cells are extremely sensitive to DNA damage, which can be caused by factors like chemicals, radiation or viruses. The experiment showed that virtually 100 percent of human embryonic stem cells treated with a DNA-damaging drug killed themselves within 5 hours, as compared to 24 hours for other types of cells.

"That's an incredibly rapid rate of death," said Deshmukh, who also is a member of the UNC Neuroscience Center and Lineberger Comprehensive Cancer Center.

The hair-trigger suicidal response is an important adaptation for embryonic stem cells, said the UNC School of Medicine researcher, because a slower response could allow DNA damage to proliferate and harm the embryo.

"Mutations that develop in these cells could be catastrophic for the developing organism, so it would make sense for these cells to be rapidly eliminated."

The key to the stem cells' quick response is that they pre-activate a critical protein called Bax, the researchers found. In most cells, Bax is kept in an inactive form, waiting for a long chain of events to rouse it into action if the cell becomes damaged enough to kill itself. In human embryonic stem cells, the team found Bax standing at attention in its active form in the Golgi apparatus, a part of the cell that processes and modifies proteins.

"What these cells do is very clever," said Deshmukh.

"They have activated Bax, but they've also parked it in a safe little compartment — the Golgi."

If the cell detects DNA damage, Bax zips over to the mitochondrion (the cell's power plant), where it signals other proteins to shut the cell down.

It's like starting a 100-yard race at the 80-yard line, said Deshmukh. You're guaranteed to get to the finish line first because you did most of the work before the race began. However, there are built-in safeguards against a hair trigger activation of death. Pre-activated Bax is housed in the Golgi keeping the protein from accidentally triggering cell death when it's not warranted.

This extreme sensitivity to DNA damage lasts only a few days during early development. After the embryonic stem cells begin differentiating into early progenitors that give rise to specific cell types (like heart cells or skin cells), Bax reverts to its inactive state.

Source: University of North Carolina School of Medicine

Contact: Les Lang

Reference:

Human Embryonic Stem Cells Have Constitutively Active Bax at the Golgi and Are Primed to Undergo Rapid Apoptosis

Raluca Dumitru, Vivian Gama, B. Matthew Fagan, Jacquelyn J. Bower, Vijay Swahari, Larysa H. Pevny, and Mohanish Deshmukh
Molecular Cell, 03 May 2012, 10.1016/j.molcel.2012.04.002

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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