Stem Cells and Hope in ALS: Part 1

by Clive N. Svendsen, Ph.D., and Geneviève Gowing, Ph.D. on Wed, 2013-05-22 09:25

Clive N. Svendsen, Ph.D.
Geneviève Gowing, Ph.D.

What hope are we seeing for stem cells in ALS?

Stem cells have two very important characteristics: They can reproduce themselves over time (self–renew), and they have the ability to replace lost or damaged cells in the body. So how can the use of stem cells affect the study and treatment of ALS? Two words: modeling (the use of models to represent human disease for use in disease mechanism research and drug development) and therapy.

Recent leaps in knowledge have vastly improved our ability to perform research using human stem cells. (For more info on the different types of stem cells, read Research Briefs: Stem Cells.)

Technology has been developed to assist in deciphering disease mechanisms and performing drug discovery using human cells that will hopefully lead to successful therapies. Moreover, the use of stem cells themselves as a therapy has gained a lot of momentum, with some recent FDA-approved clinical trials ongoing in the U.S. and elsewhere around the world — and many more surely to come. (For more, visit

However, there are many different types of stem cells (rather like there are different types of drugs) — some more powerful than others. Caution is needed when interpreting press releases or even scientific journal papers involving stem cell breakthroughs and therapies.

Disease modeling and drug discovery using stem cells

There are two main strategies used to model human diseases. One is the use of genetically modified animal models, and the second is cell culture lines generated for in vitro study.

While the generation of animal models can be challenging, some results have provided important information. One example is the mutant SOD1 transgenic mouse model of ALS, which has significantly contributed to our understanding of ALS disease processes.

However, despite the existence of this and other animal models, we still have not found an efficient therapeutic approach that can inhibit or significantly slow the progression of ALS based on drug efficacy in these models. Could it simply be because mice are not men, and the models used to date do not fully recapitulate the genetics, onset and function of a disease that occurs in human beings? This is a question often hotly debated and one that still remains an open question. (For more, read Are SOD1 Mice Good Models of Human ALS?.)

The other challenge involves the use of human cell culture models to study disease.

Up until recently, human stem cell lines were used that didn't have normal biology and certainly were not human motor neurons like those that are lost in ALS. After Jamie Thomson derived human embryonic stem (ES) cells from human embryos in 1998, however, it was possible for the first time to generate motor neurons in the culture dish. Studies using these models continue to provide crucial information on the mechanisms of motor neuron degeneration in ALS and have served to identify possible neuroprotective targets.  

In 2006, the discovery that adult cells could be reprogrammed back in time to a stem-cell-like state forever changed stem-cell-based research. The final products of this reprogramming effort are called induced pluripotent stem (iPS) cells. Similarly to how they use ES cells, investigators can use iPS cells to produce the cell types that are implicated in a disease — such as motor neurons for ALS — "in a dish." (See images below.)

In these images, iPS cell-derived motor neurons "in a dish" allow researchers to "replay" what happens in ALS. (A) Motor neurons are shown in green. (B) Motor neurons are green; those that are dying are stained red. (C) In an aggregate (clump) of cells, immature motor neurons are marked in green, more mature motor neurons in red. Images provided by Dhruv Sareen of the Cedars-Sinai iPS core.

So how has the use of disease modeling with iPS cells changed research, and why are iPS cells a big deal?

The initial product used to make iPS cells (typically a skin sample) is isolated directly from a human patient affected by the disease, alongside similar cells taken from a nonaffected "control" patient.

Prior to the advent of iPS cells, it was not possible to continuously "replay" a disease using human cells from an affected patient over and over in a dish until a solution was found. Today, it is possible! As an example, we at the Svendsen lab have shown that motor neurons can be generated from iPS cells that were produced from patients affected with spinal muscular atrophy (SMA), and showed that the motor neurons that were produced were smaller and less numerous than those of control samples.

Today, we are using this model to screen for drugs capable of slowing or reversing the disease-associated mechanisms observed in the culture dish.

It is our hope that human stem-cell-based assays will greatly assist in deciphering the mechanisms involved with motor neuron death in ALS and lead to rapid drug discovery.

Editor's note: The second part of this blog will be published on the ALSN site Wednesday, May 29, so be sure to check back for the second installment titled Stem Cells and Hope in ALS: Part 2.

About the Authors

Clive N. Svendsen, Ph.D.
Director, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, Calif.
Department of Biomedical Sciences, Cedars-Sinai Medical Center
Professor in Residence, Department of Medicine
, University of California, Los Angeles
Consultant Professor,
Department of Neurosurgery, Stanford University, Palo Alto, Calif.

Svendsen did his pre-doctoral research at both the University of Cambridge and Harvard University. After receiving his Ph.D. in neuroscience from the University of Cambridge, he continued to develop a research program in neural stem cells and neurodegeneration before moving to become Professor of Anatomy and Neurology at the University of Wisconsin. There he co-founded the Stem Cell and Regenerative Medicine Center.

He now directs the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, where 20 faculty members and almost 100 staff members are using induced pluripotent stem cells to model and treat diseases such as diabetes, hepatitis C, macular degeneration, osteoporosis and neurodegenerative disorders. His own lab is performing the world’s first combined growth factor and stem cell transplant trial for ALS, and striving to learn more about the origins and new treatments for diseases of the nervous system.

Geneviève Gowing, Ph.D.
Gowing is a project scientist in the laboratory of Dr. Clive Svendsen at the Regenerative Medicine Institute of Cedars-Sinai Medical Center in Los Angeles. She was trained in the laboratory of Dr. Jean-Pierre Julien at Université Laval, Québec City, Québec, Canada, where she studied the role of microglia in mouse models of ALS. Her work in Svendsen’s lab is focused on assessing the potential of stem-cell-based and other therapies in animal models of ALS.

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